Abstract
Background
Fertility and pregnancy-related issues are critical for young patients with breast cancer. No proper evidence exists on physicians' knowledge, practice, and attitudes on dealing with these concerns in the specific group of patients with advanced disease.
Methods
A 26-item questionnaire was administered via e-mail in December 2023 to physicians who attended the ABC6 consensus conference (virtually, November 2021) and those who were registered for the ABC7 consensus conference (Lisbon, November 2023). The questionnaire was divided into 3 main sections: 1) demographic, medical training, and background information; 2) knowledge, practice, and attitudes of physicians towards fertility preservation and pregnancy-related issues in patients with advanced breast cancer; 3) approach to hypothetical clinical cases.
Results
A total of 133 physicians completed the survey. Most reported discussing always (40.6 %) or usually (36.1 %) the possible treatment-related loss of ovarian function in patients with advanced breast cancer. Regarding fertility preservation and pregnancy-related issues, 23.3 % would always feel comfortable discussing these topics with patients, and 45.9 % would feel comfortable depending on the clinical situation. 20.3 % reported not prescribing any type of contraception, and 10–20 % would prescribe treatments that are contraindicated during pregnancy.
Conclusions
Our survey showed that many concerns exist when discussing and dealing with fertility and pregnancy-related issues in patients with advanced breast cancer. It is essential to increase physicians' awareness on how to address fertility and pregnancy-related issues in patients with advanced breast cancer, especially as oncological treatments continue to improve, resulting in longer survival and, in some cases, potential cure.
Keywords: MBC, Fertility, Pregnancy, Young patients, Survey
Highlights
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Fertility and pregnancy-related issues are critical for young patients with breast cancer.
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The survey assesses physicians' knowledge, practice, attitudes on fertility and pregnancy-related issues in advanced disease.
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About 70 % of physicians would feel comfortable in discussing these issues (45 % depending on the clincal situation).
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About 20 % of physicians do not prescribe any type of contraception to patients with advanced breast cancer.
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About 10–20 % of physicians would prescribe treatments that are contraindicated during pregnancy.
1. Introduction
Breast cancer is the major contributor to cancer burden in young women: in recent years, its incidence has increased among women younger than 40–50 years old [1,2]. Fertility and pregnancy-related issues are crucial components in the care of young women with breast cancer [3]. Over the past years, a growing body of evidence has become available to aid in the management of fertility and pregnancy-related issues, particularly in the field of breast cancer [4]. Although the guidelines advocate on discussing the risk of developing treatment-induced gonadotoxicity with all patients diagnosed during their reproductive years irrespective of the stage of the disease at diagnosis [4], the evidence supporting the different steps of the oncofertility counseling derives exclusively from patients diagnosed with early disease. As shown in several surveys, physicians’ attitudes toward oncofertility care in young women with breast cancer remain suboptimal even in the curative setting [[5], [6], [7], [8], [9], [10]].
Although metastatic breast cancer (MBC) has been historically considered an incurable condition, advances in therapeutic strategies have significantly improved survival rates and some women may be potentially cured [11]. One of the main examples is represented by HER2-positive MBC in which a constant improvement in overall survival has been observed over the past years, challenging the concept of incurable disease in some cases [[12], [13], [14]]. Another recent example in the setting of hormone receptor-positive/HER2-negative breast cancer is represented by the addition of first-line CDK4/6 inhibitors to endocrine therapy, with two trials showing for the first time a median overall survival exceeding 5 years [15,16]. Although triple-negative MBC still represents an unmet need as compared to the other subtypes, recent important advancements have been made with the introduction of immunotherapy in combination with chemotherapy in the first-line setting, the use of antibody-drug conjugates in later lines, and of PARP inhibitors in BRCA carriers [11]. Therefore, survivorship-related issues are also acquiring increasing importance in the setting of MBC [17,18]. Among them, the need to not only inform young women of the risk of treatment-induced gonadotoxicity but also to properly address fertility (including contraception) and pregnancy-related issues is becoming clinically relevant.
At the Advanced Breast Cancer International Consensus Conference 7 (ABC7), special attention was paid to this specific topic [18]. In order to evaluate the current knowledge, practice, and attitudes of physicians regarding fertility and pregnancy-related issues in young women with MBC, we conducted a survey among various specialists who attended the ABC6 and ABC7 consensus conferences.
2. Materials and methods
We developed a specific questionnaire (Supplementary Appendix 1) evaluating fertility and pregnancy-related issues in young women with MBC. The survey was administered in December 2023 to physicians who attended the ABC6 international consensus conference (virtually, in November 2021) and those who were registered to the ABC7 international consensus conference (in Lisbon, Portugal, in November 2023) [18].
Participants at these conferences included different stakeholders involved in the manamenet of MBC, including physicians from various specialties (i.e., medical oncologists, radiation oncologists, surgical oncologists, gynecologists, etc), non-medical health-care personnel, and patient advocates. Although the survey was distributed electronically to all attendees of the ABC6 and ABC7 conferences, only physicians were allowed to complete the questionnaire. Physicians who attended both the ABC6 and ABC7 conferences were allowed to complete the questionnaire only once.
2.1. Characteristics of the survey
A 26-item survey was divided into 3 main sections (Supplementary Appendix 1): 1) Demographic, medical training, and background information (9 items); 2) knowledge, practice, and attitudes of physicians towards fertility preservation and pregnancy-related issues (11 items); 3) Approach to hypothetical clinical cases (6 items).
The questionnaire was conceived and adapted based on a prior survey addressing fertility and pregnancy-related issues in breast cancer but focusing only on women with early disease [9]. The questions were developed by a team of physicians with specific expertise in the care of breast cancer in young women and the management of fertility preservation and pregnancy-related issues.
2.2. Study objectives
This survey aimed to describe physicians' knowledge on fertility and pregnancy-related issues in young patients with MBC and to investigate their practice and attitudes in the context of different hypothetical clinical cases.
2.3. Statistical analysis
The knowledge and attitudes of physicians throughout the survey were assessed using a single-select multiple-choice questions or multi-select multiple-choice questions (if the answer could be more than one option).
Primary analyses were descriptive. Median and interquartile range (IQR) were used to summarize continuous variables and percentages were used to summarize categorical variables.
To assess the level of agreement among physicians on Q21-Q26 answers, Fleiss’ kappa was performed.
All tests were two-sided and p-values of <0.05 were considered statistically significant. All analyses were performed using SAS version 9.4 and R version 4.3.1.
3. Results
A total of 133 physicians attending the ABC6 and ABC7 international consensus conferences completed the survey. The median age of responders was 46 years (IQR 38–55 years); among them, 76.7 % were female. Most of the responders were from Europe (45.9 % from Western and 39.1 % from Eastern Europe, respectively) and self-reported to be catholic (32.3 %). Most responders were medical oncologists (84.2 %), had at least 10 years of clinical practice (79.7 %), worked in a breast cancer unit (69.9 %), and evaluated at least 10 new cases per year of young women with breast cancer (80.4 %). 63.2 % of responders had at least 1 child, and 9.8 % had a parenthood project (i.e. intention to have a child in the future).
All demographic, medical training, and background information are reported in Table 1.
Table 1.
Demographic, medical training, and background information of responding physicians.
| N (%) | |
|---|---|
| Total responding physicians | 133 |
| Age, median (interquartile), years | 46 (38–55) |
| Age category | |
| <40 years | 41 (30.8) |
| 40–50 years | 42 (31.6) |
| >50 years | 50 (37.6) |
| Gender | |
| Female | 102 (76.7) |
| Male | 30 (22.6) |
| Prefer not to say | 1 (0.8) |
| Region of practice | |
| Western Europe | 61 (45.9) |
| Eastern Europe | 52 (39.1) |
| America | 8 (6.0) |
| Asia | 8 (6.0) |
| Africa | 4 (3.0) |
| Religion | |
| Catholic | 43 (32.3) |
| Protestant | 4 (3.0) |
| Muslim | 8 (6.0) |
| Hindu | 2 (1.5) |
| Jewish | 1 (0.8) |
| Atheist/none | 28 (21.1) |
| Other | 32 (24.1) |
| Prefer not to answer | 15 (11.3) |
| Children or parenthood project? | |
| No | 36 (27.0) |
| Parenthood project | 13 (9.8) |
| 1 | 19 (14.3) |
| ≥2 | 65 (48.9) |
| Specialty | |
| Medical oncology | 112 (84.2) |
| Radiation oncology | 2 (1.5) |
| Surgical oncology | 14 (10.5) |
| Gynecologists | 5 (3.8) |
| Years of clinical practice (including MD specialization) | |
| Median (interquartile), years | 17 (11–25) |
| <10 years | 27 (20.3) |
| 10–20 years | 55 (41.4) |
| >20 years | 51 (38.3) |
| Work in breast cancer unit | |
| Yes | 93 (69.9) |
| No | 40 (30.1) |
| New young breast cancer patients (≤ 40 years) every year | |
| <10 patient/year | 26 (19.6) |
| 10–50 patient/year | 66 (49.6) |
| >50 patient/year | 41 (30.8) |
3.1. Oncofertility counseling in young women with MBC
Most responding physicians were well aware of the presence of international guidelines on fertility preservation and pregnancy-related issues in patients with cancer (94.7 %), and 82.7 % of them consulted these guidelines (Table 2). Regarding the loss of ovarian function and fertility before the start of anticancer therapies, 78.9 % and 18.8 % of physicians always or usually discussed these issues with their patients affected by early breast cancer, respectively. However, these percentages decreased to 40.6 % and 36.1 % when dealing with MBC. A total of 30.9 % were not confortable to discuss about oncofertility in patients with MBC. The main concerns in discussing oncofertility in patients with MBC were the severe prognosis of the disease in most cases (35 %), the lack of data on interrupting anticancer treatments (23 %), and the lack of guidelines in dealing with this situation (12 %) (Fig. 1).
Table 2.
Oncofertility counseling in young women with advanced breast cancer.
| N (%) | |
|---|---|
| Have you ever consulted the available international guidelines on fertility preservation and pregnancy-related issues in patients with cancer? | |
| Yes | 110 (82.7) |
| No, but I know where to find these guidelines if needed | 16 (12.0) |
| No, I am not aware of available guidelines on these topics | 7 (5.3) |
| How often do you discuss the possible treatment-related loss of ovarian function and fertility in young patients with early breast cancer before starting anticancer therapies? | |
| Always | 105 (78.9) |
| Usually | 25 (18.8) |
| Rarely | 3 (2.3) |
| Never | 0 (0.0) |
| How often do you discuss the possible treatment-related loss of ovarian function and fertility in young patients with advanced breast cancer before starting anticancer therapies? | |
| Always | 54 (40.6) |
| Usually | 48 (36.1) |
| Rarely | 29 (21.8) |
| Never | 2 (1.5) |
| Would you feel comfortable discussing fertility preservation and pregnancy-related issues in young patients with advanced breast cancer? | |
| Yes, always | 31 (23.3) |
| Yes, but depending on the clinical situation (age, breast cancer subtype, recommended treatment, complete radiological response or very long stabilization of the disease, etc.) | 61 (45.9) |
| No, but I could reconsider this discussion depending on the clinical situation (age, breast cancer subtype, recommended treatment, complete radiological response or very long stabilization of the disease, etc) | 32 (24.1) |
| Never | 9 (6.8) |
Fig. 1.
Main concerns in the oncofertility counseling of patients with advanced breast cancer (multiple choice permitted).
3.2. Management of MBC during pregnancy
In patients diagnosed with breast cancer during pregnancy, most physicians would administer chemotherapy in the second and third trimesters (85.7 %), while 10.5 % would never prescribe it (Table 3). A total of 84.2 %, 82.0 %, and 87.2 % of responders would never prescribe anti-HER2 agents, endocrine-based treatment, and immunotherapy during pregnancy, respectively. For contraception in young women affected by breast cancer, male condoms, and copper intrauterine devices (IUDs) were the most commonly selected methods suggested by the responders. However, 20.3 % would not prescribe any type of contraception (Fig. 2).
Table 3.
Management of advanced breast cancer during pregnancy.
| N (%) | |
|---|---|
| Would you prescribe chemotherapy during pregnancy? | |
| Yes, in all the trimesters | 5 (3.8) |
| Yes, but only in the second and third trimesters | 114 (85.7) |
| Never | 14 (10.5) |
| Would you prescribe anti-HER2 agents during pregnancy? | |
| Yes, in all the trimesters | 4 (3.0) |
| Yes, but only in the second and third trimesters | 17 (12.8) |
| Never | 112 (84.2) |
| Would you prescribe endocrine-based treatment during pregnancy? | |
| Yes, in all the trimesters | 4 (3.0) |
| Yes, but only in the second and third trimesters | 20 (15.0) |
| Never | 109 (82.0) |
| Would you prescribe immunotherapy during pregnancy? | |
| Yes, in all the trimesters | 4 (3.0) |
| Yes, but only in the second and third trimesters | 13 (9.8) |
| Never | 116 (87.2) |
| Would you prescribe any type of contraception to pre-menopausal patients affected by advanced breast cancer? | |
| Yes | 106 (79.7) |
| No | 27 (20.3) |
Fig. 2.
Type of contraception prescribed to pre-menopausal women affected by advanced breast cancer (multiple choice permitted).
3.3. Approach to hypothetical clinical cases
Full questions, options, and answers about hypothetical clinical cases are reported in Table 4. Two cases for each breast cancer subtype were prepared.
Table 4.
Approach to hypothetical clinical cases regarding young women with advanced breast cancer.
| N (%) | |
|---|---|
| Hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC) | |
| Q21. A 32-year-old patient diagnosed with HR+/HER2- MBC (bone metastases) asks about the possibility to have a pregnancy after achieving a complete radiological response while on first-line treatment with endocrine therapy (ET) plus a CDK4/6 inhibitor (CDK4/6i) for 1 year. How would you counsel the patient? | |
| I would always discourage the patient from having a pregnancy considering her prognosis. | 45 (33.8) |
| I would potentially support the possibility to have a pregnancy but only continuing the active anticancer treatment. | 14 (10.5) |
| I would potentially support the possibility of stopping the treatment for having a pregnancy only in the case of oligometastatic de novo disease at diagnosis and durable complete radiological response or very long stabilization of the disease. | 71 (53.4) |
| I would always support the possibility of stopping the treatment for having a pregnancy. | 3 (2.3) |
| Q22. A 32-year-old patient is diagnosed with HR+/HER2- de novo MBC (bone metastases) during the 16th week of pregnancy. How would you counsel the patient? | |
| I would always support the possibility of having an abortion considering her prognosis. | 12 (9.0) |
| I would discuss the possibility to continue the pregnancy by offering a first-line treatment with endocrine therapy plus a CDK4/6i during pregnancy. | 11 (8.3) |
| I may discuss the possibility to continue the pregnancy by offering chemotherapy until delivery but clearly informing the patient about the prognostic implication of delaying the standard treatment (i.e. ET plus a CDK4/6i) after pregnancy. | 93 (69.9) |
| I may discuss the possibility to continue the pregnancy without offering anticancer therapies only whenever a preterm delivery is feasible following a clear discussion on her prognosis. | 17 (12.8) |
| N (%) | |
|---|---|
| Triple-negative (TN) MBC | |
| Q23. A 30-year-old patient diagnosed with TN MBC de novo is under first-line treatment with capecitabine for 3 months. She has just discovered to be at week 10 of gestation. How would you counsel the patient? | |
| I would always support the possibility of having an abortion considering her prognosis and the risk of malformations with first trimester exposure to this treatment. | 87 (65.4) |
| I would potentially support the possibility to continue the pregnancy but only continuing the active anticancer treatment. | 6 (4.5) |
| I may discuss the possibility to continue the pregnancy by stopping the therapy until the second trimester, then offering another type of chemotherapy until delivery. | 34 (25.6) |
| I would potentially support the possibility of stopping the treatment for continuing the pregnancy only in the case of oligometastatic de novo disease at diagnosis and durable complete radiological response or very long stabilization of the disease. | 6 (4.5) |
| Q24. A 30-year-old patient is diagnosed with TN PD-L1+de novo MBC during the second trimester of pregnancy. How would you counsel the patient? | |
| I would always support the possibility of having an abortion considering her prognosis. | 20 (15.0) |
| I would discuss the possibility to continue the pregnancy by offering a first-line treatment with chemotherapy plus immunotherapy during pregnancy. | 7 (5.3) |
| I may discuss the possibility to continue the pregnancy by offering chemotherapy alone until delivery but clearly informing the patient about the prognostic implication of delaying the standard treatment (i.e. chemotherapy plus immunotherapy) after pregnancy. | 102 (76.7) |
| I may discuss the possibility to continue the pregnancy without offering anticancer therapies only whenever a preterm delivery is feasible following a clear discussion on her prognosis. | 4 (3.0) |
| N (%) | |
|---|---|
| Hormone receptor-negative (HR-)/HER2-positive (HER2+) MBC | |
| Q25. A 35-year-old patient diagnosed with HR-/HER2+MBC asks about the possibility to have a pregnancy after achieving a complete radiological response while on first-line treatment with pertuzumab plus trastuzumab for 5 years. How would you counsel the patient? | |
| I would always discourage the patient from having a pregnancy considering her prognosis. | 31 (23.3) |
| I would potentially support the possibility to have a pregnancy but only continuing the active anticancer treatment. | 7 (5.3) |
| I would potentially support the possibility of stopping the treatment for having a pregnancy only in the case of oligometastatic de novo disease at diagnosis and durable complete radiological response or very long stabilization of the disease. | 68 (51.1) |
| I would always support the possibility of stopping the treatment for having a pregnancy in this situation. | 27 (20.3) |
| Q26. A 35-year-old patient diagnosed with HR-/HER2+MBC is under first-line treatment with pertuzumab plus trastuzumab. She has just discovered to be at week 10 of gestation. How would you counsel the patient? | |
| I would always support the possibility of having an abortion considering her prognosis and the risk of malformations with first trimester exposure to this treatment. | 78 (58.6) |
| I would potentially support the possibility to continue the pregnancy but only continuing the active anticancer treatment. | 3 (2.3) |
| I may discuss the possibility to continue the pregnancy by stopping the therapy until the second trimester, then offering chemotherapy until delivery but clearly informing the patient about the prognostic implication of changing the standard treatment. | 38 (28.6) |
| I would potentially support the possibility of stopping the treatment for continuing the pregnancy only in the case of oligometastatic de novo disease at diagnosis and durable complete radiological response or very long stabilization of the disease. | 14 (10.5) |
In hormone receptor-positive/HER2-negative MBC, 53.4 % of physicians would potentially support the possibility of stopping the treatment for having a pregnancy only in the case of oligometastatic de novo disease at diagnosis and durable complete radiological response or very long stabilization of the disease. In patients diagnosed during the 16th week of gestation, 69.9 % of physicians may discuss the possibility of continuing the pregnancy by offering chemotherapy until delivery but clearly informing the patient about the possible prognostic implications of delaying the standard treatment (i.e., endocrine treatment plus a CDK4/6 inhibitor) until after pregnancy.
In triple-negative MBC, most physicians (65.4 %) would always support the possibility of having an abortion if a patient is discovered to be at week 10 of gestation during first-line treatment with capecitabine, considering her prognosis and the concern of malformations with first-trimester exposure to this treatment. In the case of a novel diagnosis of triple-negative MBC during the second trimester of pregnancy, 76.7 % of physicians may discuss the possibility of continuing the pregnancy by offering chemotherapy alone until delivery but clearly informing the patient about the possible prognostic implications of delaying the standard treatment (i.e., chemotherapy plus immunotherapy) until after pregnancy.
Regarding cases affected by HER2-positive disease, 51.1 % of physicians would potentially support the possibility of stopping the treatment for having a pregnancy only in the case of oligometastatic de novo disease at diagnosis and with a durable complete radiological response or very long stabilization of the disease (for example, while on first-line treatment with pertuzumab plus trastuzumab for 5 years). If a patient under treatment with pertuzumab plus trastuzumab is discovered to be at week 10 of gestation, 58.6 % of physicians would always support the possibility of having an abortion considering her prognosis and the fear of malformations with first-trimester exposure to this treatment.
Fleiss' Kappa is a statical measure to assess the concordance, with a 6 level of agreement (from <0 to 1, with <0 resulting in a poor agreement and 1 in a perfect one). Overall, of the 133 participants who answered these 6 clinical situations, the Fleiss' Kappa's value was 0.134, resulting in a slight agreement, the second worst out of six agreement levels for kappa.
4. Discussion
To the best of our knowledge, this is the first survey focusing specifically on physicians’ knowledge, practice, and attitudes on fertility and pregnancy-related issues in the specific cohort of young women affected by MBC.
Fertility remains a fundamental concern for many young women, even in the context of MBC, due to its profound impact on identity, quality of life, and long-term life planning. For some, the ability to conceive or simply preserve fertility offers a sense of normalcy and future in the face of a life-threatening diagnosis. As treatments improve and survival prolongs, it is starting to become a realistic concern also in the setting of advanced breast cancer. In interpreting the results of our survey, it should be specified that the answers were derived from physicians attending two international conferences specifically focused on MBC [18]. Despite the clinical-psychological burden of dealing with MBC, almost three-quarters of responding physicians reported discussing the topic of premature ovarian insufficiency (POI) with these patients, and about two-thirds would feel comfortable discussing fertility preservation and pregnancy-related issues with young patients with MBC. On the other hand, roughly 20 % did not routinely prescribe contraceptive methods to these patients, and about 10–20 % of physicians prescribed treatments contraindicated during pregnancy, resulting in controversial approaches to the hypothetical clinical cases that we prepared.
As highlighted in the guidelines, all patients with cancer diagnosed at reproductive age should receive comprehensive oncofertility counseling as early as possible after diagnosis, regardless of the type and stage of the disease [4]. In our survey, the majority of responding physicians reported always or usually discussing (78.9 % and 18.8 %, respectively) these issues with their patients with early disease before starting anticancer treatments. These percentages appear to be higher than those shown in prior surveys [9,10,19]. This result may be related to participants' selection as well as to the recent growing availability of reassuring safety data about fertility preservation and pregnancy after early breast cancer [[20], [21], [22], [23], [24], [25]]. However, when the same question was asked about the counseling of patients with MBC, the percentage of responding physicians discussing this issue dropped, with more than 20 % of them rarely or never discussing POI and fertility in the advanced setting. The main reasons for not feeling comfortable discussing fertility and pregnancy-related issues in young patients with MBC were mainly related to the severe prognosis and the lack of data or guidelines about interrupting anticancer treatments. Considering that also in patients with early breast cancer, prior surveys showed that their prognosis was considered a barrier in physicians’ willingness to perform oncofertility counseling [8,26,27], it is not surprising to observe these concerns in the MBC setting. On the other hand, since the question is related to both ovarian function and fertility, we cannot discern if some physicians are used to discuss POI and its subsequent menopause-related consequences without taking into account the fertility aspect. As expected, the lack of proper safety evidence in this setting represents another important barrier. More efforts are needed to collect gonadotoxicity and reproductive data in the trials investigating new effective treatment strategies that may lead to prolonged survival and/or potential cure also for patients with MBC [28].
Chemotherapy in the second and third trimesters of pregnancy represents the only systemic treatment that can be offered to patients diagnosed with breast cancer during pregnancy [29]. While 85.7 % of responding physicians would prescribe chemotherapy during the second and third trimesters of pregnancy, 3.8 % would offer it also in the first trimester, while 10.5 % would never administer it in pregnant patients. Chemotherapy use during the first trimester is associated with a high incidence of fetal malformations in about 14 % of cases and thus it is contraindicated; on the contrary, a growing amount of evidence has shown the maternal and fetal safety of cytotoxic therapy when given in the second and third trimesters [[30], [31], [32]].
Anti-HER2 agents and, in general, targeted drugs are contraindicated during pregnancy [33]. Nevertheless, in our survey, 15.8 % of responding physicians would offer anti-HER2 agents to pregnant patients, particularly in the second and third trimesters. A systematic review by Andrikopoulou et al., including 28 patients treated with trastuzumab during pregnancy (17 in the metastatic setting) reported oligohydramnios or anhydramnios in two-thirds of cases, with a lower risk in the case of first-trimester exposure (16.7 % vs 70.8 %) [34]. Newborns were healthy in 75 % of cases exposed in the first trimester as compared to 41.7 % of those exposed in the second or third trimesters [34]. On the other hand, pregnancy should not be prematurely interrupted if trastuzumab is accidently administered during the first trimester: differently from chemotherapy and small molecules, no malformation has been described with monoclonal antibodies that, being large molecules, require active transportation to cross the placenta [35].
Endocrine-based therapy is contraindicated during pregnancy [29]. Tamoxifen has a known teratogenic effect [36]. Nevertheless, some authors are not so strict about pregnancy interruption in the case of exposure to tamoxifen during pregnancy, but they suggest discussing the risks with the patient [37,38]. A case report of tamoxifen (20 mg daily) exposure throughout pregnancy in a patient with MBC resulted in a normal newborn, despite a difficult gestation (patients developed lethargy, bone pain, weight loss, and neurological weakness or pals) [39]. In MBC, CDK4/6 inhibitors added to endocrine therapy are the current standard of care in the first-line setting for almost all patients: no data exist on exposure to this treatment during pregnancy [40].
Despite immunotherapy registering the highest “never use” answer in our survey (87.2 %), 12.8 % of physicians would consider it during pregnancy. Due to the changes in placenta permeability throughout pregnancy and their large size, similar considerations as for monoclonal antibodies would apply to immune checkpoint inhibitors [41]. Overall, poor data are available on their use and toxicities during pregnancy [42]. A recent case report presented severe immune-related enteritis in the newborn born after the mother received adjuvant pembrolizumab starting from the 9th week of pregnancy [43]. Although the enteritis was successfully treated with steroids and infliximab, this emphasizes the contraindication to use immunotherapy during pregnancy.
Hormonal-based contraceptive methods should be avoided in patients with breast cancer with the indication of transitioning to non-hormonal strategies after diagnosis. However, an analysis from the Cancer Toxicity (CANTO) study reported that less than half of patients used contraception after diagnosis of breast cancer [44]. ABC6 and 7 guidelines recommend that all patients with MBC should be advised on the importance of effective non-hormonal contraception, regardless of subtype, with clear communication about the risks pregnancy poses to both the mother and the fetus during treatment [18]. In our survey, 79.7 % of physicians responded affirmatively, which means that more than 20 % of them do not regularly prescribe any type of contraception. This could also be related to the fact that all patients affected by hormone receptor-positive advanced breast cancer are expected to undergo gonadotropin-releasing hormone agonist, although it should not be considered a valid contraceptive method [[45], [46], [47]]. Because hormonal contraception should be avoided, a barrier method or a IUDs are preferred: these two methods were the preferred types of contraception by physicians responding to our survey.
Complex clinical cases not fitting into the current guidelines were asked to physicians.
For hormone receptors-positive/HER2-negative breast cancer, most physicians (53.4 %) agreed to potentially support an interruption of treatment to start a pregnancy in case of oligometastatic de novo diseases and durable response. Decket et al. performed a retrospective analysis about the discontinuation of CDK4/6 inhibitors in patients with MBC and stable disease for at least 6 months, continuing endocrine therapy alone: out of 22 evaluated patients, 6 had a disease progression (1 local and 5 distant recurrences) after a median duration of 9.5 months of monotherapy [48]. However, to attempt pregnancy, endocrine therapy should also be discontinued. The POSITIVE trial provided reassuring results at short-term follow-up about the safety of temporarily interrupting adjuvant endocrine treatment to attempt pregnancy in patients with early disease and a relatively low/intermediate risk of recurrence [25]. However, there is no data about following the same approach in patients with MBC, not even in those with oligometastatic disease treated with curative intent or without evidence of disease after the start of therapy.
The majority of responding physicians (69.9 %) agreed to discuss the possibility of continuing pregnancy if MBC with bone-only metastases was diagnosed at the 16th week of gestation by offering chemotherapy until delivery before starting endocrine therapy. However, although this is the only possible approach to allow pregnancy continuation while offering a systemic treatment to the patient, it should be clearly discussed that first-line endocrine therapy plus a CDK4/6 inhibitor provides overall survival benefits and is superior to chemotherapy [15,49,50].
For triple-negative MBC, the first case hypothesized an unintentional pregnancy at week 10 of gestation after 3 months of capecitabine: 65.4 % of responders would suggest having an abortion because of both the risk of malformation with chemotherapy exposure during the first trimester and considering the poor prognosis of the mother. Before having this discussion with the patient, her partner, and caregivers, it is important to verify if there are malformations and their willingness to continue the pregnancy. In these circumstances, particularly when receiving treatment with limited gonadotoxic effect, it is highly relevant to properly discuss the need to undergo contraception. In addition to the contraindication to use immunotherapy, no data are available about the safety of antibody-drug conjugates during pregnancy and the omission of these treatments could further compromise patient outcomes.
The second case was about the detection of pregnancy in the second trimester in a young lady with newly diagnosed triple-negative PD-L1 positive de novo MBC. Considering the safety of chemotherapy after the first trimester, its use while continuing the pregnancy can be discussed; nevertheless, immunotherapy should be avoided as correctly stated by 87.2 % of responding physicians, and the patient should be aware of the suboptimal treatment she would receive until the delivery.
For hormone receptor-negative/HER2-positive MBC with durable response and oligometastatic de novo disease, half of the physicians (51.1 %) agreed to temporarily discontinue targeted agents for allowing a pregnancy. Unfortunately, even if cases of prolonged complete response after anti-HER2 therapy withdrawal are reported, the long-term outcomes of this approach are unknown [[51], [52], [53]]. A retrospective study showed that among the 15 patients who discontinued trastuzumab after a durable complete response, 2 had a recurrence (13.3 %) [54]. Another retrospective study reported a 14.8 % relapse rate among 27 patients who stopped trastuzumab after achieving a complete response, with a median duration of treatment of 5.1 years [55]. More data will become available in the future with the STOP-HER2 study evaluating the safety of withdrawing anti-HER2 maintenance treatment in patients with a durable, exceptional response [56]. However, in the case of disease progression, while the patient is pregnant, she should be made aware that anti-HER2 agents, including ADCs, can be re-started only after delivery.
The second case addressed the issue of an accidental pregnancy at 10 weeks of gestation during first-line treatment with pertuzumab plus trastuzumab: in this setting, most physicians (58.6 %) would recommend the possibility of having an abortion because of the risk of malformations, especially during the first trimester. Nevertheless, molecular antibodies that exceed 100 kDa cannot cross the placenta through diffusion but need a specific receptor-mediated mechanism that becomes functional starting from the 14th week of pregnancy [35]. So far, no malformations have been reported with these agents; however, important complications (e.g. oligohydramnios) have been reported with proactive use in the second and third trimesters. Hence, in patients with MBC, the potential prognostic implications of withdrawing an effective targeted treatment for more than 6 months until delivery should be clearly discussed.
Eventually, the responders’ agreement on clinical cases, calculated with Fleiss K, resulted in a “slight agreement” that underscores how it is challenging and controversial to approach those clinical scenarios even when selecting highly specialized responders.
Our analysis has some important limitations. First, the survey was administered only among physicians who specialized in breast cancer treatment and attended an event dedicated to advanced breast cancer. Therefore, our results may have a selection bias of experts in the field, and the results may be very different and knowledge less existent amongst physicians involved also in the treatment of other cancers or other healthcare professionals. Second, despite simulating clinical cases, it is hard to address all the possible issues faced in this field. Finally, the multiple-choice format of the survey may limit the range of responses, resulting in partial feedback and leaving no room for more complex arguments.
5. Conclusions and next steps
In conclusion, this survey aiming to investigate physicians’ knowledge, attitudes, and clinical approaches to fertility and pregnancy-related issues in young women affected by MBC showed that many concerns exist when discussing and dealing with these issues in this special clinical setting. Current recommendations to address these topics are available in early breast cancer, with limited evidence specifically in the metastatic setting. This gap leaves many clinicians uncertain about how best to counsel patients, contributing to inconsistent practices and potential missed opportunities for informed patient-centered care. Our findings underscore an urgent need for dedicated research efforts in this area. These include prospective multicenter observational studies collecting data on fertility and pregnancy-related issues in young women affected by MBC. Additionally, future clinical trials evaluating new treatments for MBC should incorporate fertility-related endpoints, including gonadotoxicity and reproductive outcomes. Targeted educational initiatives for oncologists and multidisciplinary teams are essential to build confidence in addressing fertility and pregnancy-realated concerns, even when definitive evidence is lacking. These programs should emphasize non-hormonal contraception strategies, appropriate treatment timing, and patient-centered communication. Ultimately, as treatments for MBC continue to improve, offering prolonged survival and even potential cure in selected cases, it becomes increasingly vital to translate lessons learned from early breast cancer into the advanced setting. Raising awareness and equipping healthcare providers with appropriate knowledge and tools will ensure that young women with MBC are not overlooked but are instead fully supported in exploring their reproductive goals and making informed choices about their future.
CRediT authorship contribution statement
Simone Nardin: Writing – review & editing, Writing – original draft, Methodology, Investigation, Data curation, Conceptualization. Luca Arecco: Writing – review & editing, Writing – original draft, Methodology, Conceptualization. Virginia Delucchi: Writing – review & editing, Writing – original draft, Formal analysis, Data curation. Eva Blondeaux: Writing – review & editing, Writing – original draft, Formal analysis, Data curation, Conceptualization. Mihaela Stana: Writing – review & editing. Luciana de Moura Leite: Writing – review & editing. Luiza Nardin Weis: Writing – review & editing. Giang Pham Hoang: Writing – review & editing. Arianna Daneri: Writing – review & editing. Francesca Bruzzone: Writing – review & editing. Arianna Meacci: Writing – review & editing. Chiara Molinelli: Writing – review & editing. Maria Grazia Razeti: Writing – review & editing. Martina Perrone: Writing – review & editing. Shani Paluch-Shimon: Writing – review & editing. Ann H. Partridge: Writing – review & editing. Fatima Cardoso: Writing – review & editing, Supervision. Tanja Spanic: Writing – review & editing. Joanna Kufel-Grabowska: Writing – review & editing, Visualization, Supervision, Conceptualization. Matteo Lambertini: Writing – review & editing, Writing – original draft, Methodology, Investigation, Data curation, Conceptualization.
Funding
The study was partly supported by the Italian Association for Cancer Research (AIRC grant MFAG 2020 ID 24698). The funder of the study had no role in study design, data collection, analysis, interpretation, writing of the report, or decision to publish the manuscript and they had no access to the data.
Declaration of competing interests
LA: travel grant from AstraZeneca; research funding (to the Institution) from Gilead outside the submitted work.
EB: speaker fee from Eli Lilly, funding (to the institution) from Gilead outside the submitted work.
CM: consultant for Daiichi Sankyo; speaker honoraria from Accademia Nazionale di Medicina; Medical Writing fee from Seagen; travel support for attending conferences from Menarini.
MGR: personal fees from Daiichi-Sankyo, non-financial support from Sophos Biotech.
FC: consultancy role for Amgen, Astellas/Medivation, AstraZeneca, Bayer, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genentech, Gilead, GlaxoSmithKline, Iqvia, Macrogenics, Medscape, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, prIME Oncology, Roche, Sanofi, Samsung Bioepis, Seagen, Teva, Touchime. Given her role as Editor-in-Chief, FC had no involvement in the peer-review of this article and has no involvement in the peer review of this article and has no access to information regarding its peer review.
JKG: speaker fee and travel grants from Eli Lilly, AstraZeneca, Roche, Swixx, Pfizer, Novartis, Gilead, Exact Sciences.
ML: advisory role for Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Gilead, MSD, Exact Sciences, Pierre Fabre, Menarini; speaker honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Libbs, Daiichi Sankyo, Takeda, Menarini, AstraZeneca; travel Grants from Gilead, Daiichi Sankyo, Roche; research funding (to the Institution) from Gilead all outside the submitted work.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.breast.2025.104479.
Appendix A. Supplementary data
The following is/are the supplementary data to this article.
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