Author:

Camilla Fiz

Abstract

Cancer, pregnancy, and fertility have been a taboo for many years, but things are improving. Patients who develop a cancer in their childbearing years now have many options for preserving their fertility. Moreover, the belief that pregnancy after cancer is dangerous has been demonstrated to be untrue. All this is the result of a complex movement, involving the increase in the number of cancer survivors, improvements in oncological therapies and augmented awareness of their long-term effects, as well as the growing interest of clinicians in this area. The multidisciplinary field of pregnancy in cancer and oncofertility was born in the United States and spread to Europe in the early 2000s, with Italy playing a key role. Step by step, many uncertainties have been clarified and numerous national and international guidelines have been published to help physicians to assist and support cancer patients in their decisions about pregnancy and fertility preservation. However, while the research activity keeps going on, in several cases patients still do not receive an appropriate information and communication on this issue, because of coordination difficulties and clinicians’ attitude.

Introduction

The issue of cancer during pregnancy and fertility grew in importance over the last 20 years and is now extremely topical. Thanks to treatments and screening, the number of cancer survivors has augmented, as well as the incidence of cancer in young people (Zhao et al., 2023). At the same time, the age when people decide to have a child is getting older (EUROSTAT, 2024), with a proportional decrease in fertility. Instead, cancer during pregnancy is a relatively rare phenomenon, occurring in 1 in 1’000 pregnancies, but its incidence is expected to rise in the coming years (Silverstein et al., 2020). All this means that more women, and even men, could develop a cancer in the years when they are more likely to start a family.

However, if yesterday cancer was seen as a death sentence, especially during a pregnancy, and oncology patients were discouraged from having children after therapy, today things are getting better. Between the late 1990s and the 2000s a strong movement, combining the efforts of patients and clinicians, has led to the birth of a community that had connected the dots among several disciplines, such as oncology, gynaecology, and psychology. This multidisciplinarity has been the only way to develop guidelines to support men and women with cancer that want to preserve their fertility or manage a pregnancy. Research into fertility pregnancy and tumours began in the United States, in particular focused on breast cancer. Then it spread throughout Europe, including Italy, which has played a key role in its development.

From cancer victims to cancer survivors

In the United States, the number of cancer survivors rose from 3 million in the 1970s to 7 million by the end of the 1980s (Fobair et al., 2009). Survivorship was indeed becoming a growing phenomenon that led to many consequences. For clinicians, this has arisen new questions about the impact of chemotherapy and radiotherapy on quality of life and long-term effects, including those on male and female fertility. For instance, it became evident that cancer therapies can cause sterility in both genres. In men it was associated with erectile dysfunction, ejaculatory difficulties, oligospermia, while in women with imbalance in FSH and LH serum levels (Dow, 1991). Later, also gonadotoxicity, premature menopause, ovarian disfunction and insufficiency and other side effects were considered (Condorelli et al., 2019). For patients, the creation of the first National Coalition for Cancer Survivorship (NCCS) in New Mexico, in 1986, changed their public image. For the first time, they went through being considered cancer victims to being survivors. This organisation also began to see patients as people who needed support on many levels, psychological, physical, or legal, in addition to the medical ones. In the following years, this movements went out of national boundaries to influence other countries. This was the case in Italy, for example, where Umberto Veronesi conceived the idea of an organisation of women fighting breast cancer, which became Europa Donna in 1993. Since the 2000s, this has been followed by many other European organisations, also pointed towards oncofertility, that are still crucial for raising awareness and supporting cancer patients.

The birth of a new scientific movement

Until the 1990s the interest of scientific community in cancer during pregnancy and oncofertility has been marginal and mostly located in the United States, where a few clinicians became ‘ultra-specialist’ in treating women with breast cancer during pregnancy, but even there they were sparse in the territory (Fiorica, 1994). “In the past, hair loss, vomiting, nausea, or the risk of relapse were the topics that doctors discussed with patients when they talked about the effects of chemotherapy. Fertility was avoided, it was associated with sexuality,” Fedro Peccatori says, referring to the situation in Italy in the early 2000s. He has been one of the first clinicians involved in the study of pregnancy in cancer and fertility, and he is currently a medical oncologist at the European Institute of Oncology (IEO), located in Milan, in Italy. “This topic was highly under-addressed and for some even a taboo!”, Hatem Azim adds, a medical oncologist at the Cairo Cure Oncology Center. He started working on oncofertility with Fedro Peccatori in 2008, when he moved from Cairo to IEO in Milan thanks to a grant from the European School of Oncology (ESO). The underestimation of the topic was exacerbated by an overall lack of experience in the field. “The lack of data to guide how to manage such cases rendered the physician not at ease to handle such discussions with patients,” Hatem Azim says: “Physicians were mostly or may be only concerned with helping their patients survive their disease, and not weighing in the importance of quality-of-life matters”. As a result, women undergoing cancer therapy were left on their own, not knowing where to turn for fertility counselling.

Over time, along with the improvements of treatments, the increase of survivors, and the patients’ organisations, the interest of scientific community in oncofertility gradually augmented. In 2006, the American Society of Clinical Oncology (ASCO) published the first report to guide the practice of oncologists on fertility’s preservation during cancer (Lee et al., 2006). The movement spread in Europe in the same years. “At a certain point, the issue of fertility and pregnancy during cancer had become unavoidable”, Fedro Peccatori says. “There has been a large movement of scientific community, involving countries like Europe, Israel, the United Kingdom”. Scientists and clinicians started approaching this field by different perspectives, such as Americans from the reproduction medicine. At the University of Leuven, in Belgium, the research group of Frédéric Amant, now a gynaecological oncologist at the Netherlands Cancer Institute in Amsterdam, was working on management of cancer during pregnancy. In the 2010s also the Swedish group of Kenny Rodriguez-Wallberg at the Karolinska Institute, in Stockholm, contributed to compare data on oncofertility in large groups of patients. Whereas, in Italy several research groups have pioneered this topic since the early 2000s.

The Italian case

Italy has probably played a key role in this field because of its important oncology tradition, related to the heritage of Gianni Bonadonna and Umberto Veronesi, and the overall context, such as the legal system. In 2004 the establishment of the Law 40, prohibiting the freezing of embryos, indirectly promoted the clinical practice of freezing oocytes. “In Italy the oocyte freezing was more advanced than in other countries where the embryo freezing was allowed” Fedro Peccatori comments: “It was easy to collect oocytes before cancer treatment, as it has been the case with male sperm for many years”. However, as often happens, contextual reasons have interrelated with personal ones. This is the case of oncologist Lucia Del Mastro, who in 2001 founded the first Italian Unit of Oncofertility at the San Martino Polyclinic Hospital where she currently works. After she had studied the ovarian toxicity of chemotherapy, she decided to address her work on fertility issues. “One year before the foundation of the unit, my twins were born. This is no coincidence,” she says: “Motherhood has drastically changed my life and made me think about the difficulties a young woman with cancer has in accepting the loss of fertility because of treatments”. When she moved from Naples to Genoa there was nothing about oncofertility, but she found a fertile place to create something new, collaborating with Paola Anserini, gynaecologist expert in Assisted Reproductive Technology (ART). As Peccatori’s group did a few years later, they started working on a special programme for cancer patients, where they could receive in-depth fertility counselling, explore all the options available, and then proceed with treatment. Usually, more than technical the main problem was to coordinate the work in a short time, since at the counselling cancer patients need a quick inference to start the treatment without too much delay.

Thousands of unknowns

In parallel to this kind of work, the research activity was going on, opening up new collaborations with other European centres. The main purpose was understanding the long-term effect of cancer therapy better and looking for new strategies to manage cancer during pregnancy and preserve fertility. Most of studies were focused on women, whose reproductive system is more complex than men’s, and in particular on breast cancer, the most common female cancer in the worldwide. “Thanks to the research and data collection at an international level, many unknowns have been clarified over time,” Fedro Peccatori says. For instance, initially, the two-weeks delay and the hormonal stimulation for oocyte cryopreservation was thought to be dangerous, and pregnancy after breast cancer was associated with a higher risk of relapse. In both cases, this was found not to be true. Rather, it was seen that women who try to get pregnant after breast cancer have a higher chance of surviving without recurrences or other adverse events, compared to those who do not (Lambertini et al., 2021).

In addition to the cryopreservation of oocytes, a non-invasive approach was first developed by the research group of Lucia Del Mastro in the mid 2000s. This was the LH-RH analogue treatment aimed to reducing gonadotoxicity and preserve ovarian function during breast cancer chemotherapy. As she tells, the project started with a simple idea: “Considering that chemotherapy is more toxic on high proliferative tissues, such as ovaries, we hypothesised that making them quiescent during chemotherapy could have a protective effect,” Lucia Del Mastro tells. Therefore, in clinical study of phase II and III they tested goserelin and triptorelin, two LH-RH analogues that interrupt the ovaries’ production of oestrogens, on women before chemotherapy (Del Mastro et al., 2006, 2011). The results were promising, as triptorelin was shown to reduce the likelihood of menopause after treatment compared to the control group, without affecting the success of oncological therapy. LH-RH analogues are now included in national and international guidelines, but initially some physicians in the United States, experts in oocyte cryopreservation, were opposed to this approach. This led to a heated debate in the scientific community. “Maybe they saw a contraposition between the two approaches,” Lucia Del Mastro tells: “However, there is no competition”. They are different tools with different activities. LH-RH analogues are used in addition to cryopreservation strategies or when these are not available.

Guidelines and reticence

As a matter of fact, all these studies have led to define European and national guidelines, such as those of the European Society of Human Reproduction and Embryology (ESHRE, 2020), as well as to numerous congresses and opportunities to meet and update. All these tools are planned to help clinicians effectively manage fertility or pregnancy in cancer patients. Today, in Europe a cancer patient in childbearing age is indeed expected to receive an in-depth counselling to understand which the best alternative is to preserve fertility. For women, overall, there are the cryopreservation of the ovarian tissue, the oocytes, or the embryo (even if this is not allowed everywhere). Otherwise, during therapy they can undergo LH-RH analogues or, after treating, techniques of Assisted reproductive technology (ART). Similarly, a man can go for cryopreservation of semen or testicular tissue. The itinerary and the final choice should be tailored on patients’ needs, age, clinical history, and physiological characteristics, as the risk of gonadotoxicity, and it should involve a psychological support.

Despite all these recommendations, many patients in several European countries still lack appropriate support and communication about fertility before and after cancer treatment, although the situation has improved. The problem is to coordinate the work of different areas in a short time, often in a context of personal or ART’s structures shortages, but it is also related to physicians’ attitude. According to a study conducted in Germany, in the early 1980s, almost the 70% of cancer patients have never addressed fertility’s topic, before treatment, while in the early 2000s it was decreased to 50% (Hohmann et al., 2011). A more recent study on breast cancer in 2022 found that 40% and almost 54% of clinicians involved in breast cancer didn’t know the international guidelines on fertility preservation and pregnancy in survivors respectively. In addition, 21,2% of physicians thought that pregnancy in breast cancer survivors may increase the risk of recurrence (Khan et al., 2022). As Matteo Lambertini, author of the latter study, explains: “Many clinician oncologists are still reticent to suggest women having children after breast cancer treatment. Hormones produced during pregnancy are thought to stimulate again the growth of tumoral cells”. He is an oncologist at the San Martino Polyclinic Hospital and collaborator of Lucia Del Mastro, Fedro Peccatori and Hatem Azim.

The belief that the relationship between breast cancer and pregnancy is dangerous is an old one. It traces back at least to 1880, when the American pioneer surgeon Samuel Gross noted that when cancer was associated with pregnancy, “its growth was wonderfully rapid and its course excessively malignant” (Lethaby et al., 1996). Matteo Lambertini states: “This belief has been around for many years, but it has never been backed up by real scientific evidence. Currently, the most important studies show that after treatment and a certain waiting period, women can safely become pregnant without an increased risk of relapse.” In this scenario, cancer patients’ association still play a key role in sensibilize and make information around fertility’s issues.

Furthering the known and exploring new perspectives

While a part of the scientific community struggle with keeping up, another part is furthering the study of pregnancy during cancer and fertility in many directions. For instance, Matteo Lambertini with his colleagues has gone on investigating the safety of pregnancy, but this time, in women that present the BRCA, that notoriously predisposes to develop earlier many tumours, involving breast and ovarian cancer (Lambertini et al., 2024). Another research field is aimed to testing the effect on fertility of new drugs and therapies, such as those of immune checkpoint inhibitors on male testicular function and sperm production (Ntemou et al., 2024), or of PARP inhibitors in women with BRCA mutation and breast cancer.

Essentially, the major advances in the field are shown by the POSITIVE trial, led by Olivia Pagani from the Oncology Institute of Southern Switzerland and Aaron Goldhirsch from the IEO, which also finds the collaboration of the physicians mentioned, Fedro Peccatori, Frédéric Amant and Hatem Azim (Partridge et al., 2023). This study has evaluated the possibility to interrupt the hormonal therapy – that need 5 years at least – to attempt pregnancy in women with breast cancer. Consequently, “women have to wait until the end of the therapy to attempt pregnancy. As the fertility potential decline by age, waiting that long would render pregnancy not feasible,” Hatem Azim concludes. “The early results of the POSITIVE trial show the short-term safety of this approach, and thus could open the door for hundreds of thousands of women worldwide to fulfil their motherhood dream, without compromising their breast cancer outcome”.

Conclusion

Over the last 20 years, research into cancer, pregnancy and fertility made great strides. Thanks to a multidisciplinary approach, it has been possible to plan specific ways to help and support young cancer patients to preserve their fertility or to try to conceive during or after treatment. However, this type of path is not effectively available everywhere because of the difficulties in managing such a programme and a certain reluctance on the part of clinicians.

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Short bibliography

Del Mastro, L., Boni, L., Michelotti, A., Gamucci, T., Olmeo, N., Gori, S., Giordano, M., Garrone, O., Pronzato, P., Bighin, C., Levaggi, A., Giraudi, S., Cresti, N., Magnolfi, E., Scotto, T., Vecchio, C., & Venturini, M. (2011). 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. JAMA, 306(3).

Lambertini, Matteo, Eva Blondeaux, Elisa Agostinetto, Anne-Sophie Hamy, Hee Jeong Kim, Antonio Di Meglio, Rinat Bernstein Molho, et al. (2024) Pregnancy After Breast Cancer in Young BRCA Carriers: An International Hospital-Based Cohort Study. JAMA 331, fasc. 1: 49.

Lee, S. J., Schover, L. R., Partridge, A. H., Patrizio, P., Wallace, W. H., Hagerty, K., Beck, L. N., Brennan, L. V., & Oktay, K. (2006). American Society of Clinical Oncology Recommendations on Fertility Preservation in Cancer Patients. Journal of Clinical Oncology, 24(18), 2917–2931.

Partridge, A. H., Niman, S. M., Ruggeri, M., Peccatori, F. A., Azim, H. A., Colleoni, M., Saura, C., Shimizu, C., Sætersdal, A. B., Kroep, J. R., Mailliez, A., Warner, E., Borges, V. F., Amant, F., Gombos, A., Kataoka, A., Rousset-Jablonski, C., Borstnar, S., Takei, J., … Pagani, O. (2023). Interrupting Endocrine Therapy to Attempt Pregnancy after Breast Cancer. New England Journal of Medicine, 388(18), 1645–1656.

The ESHRE Guideline Group on Female Fertility Preservation, Anderson, R. A., Amant, F., Braat, D., D’Angelo, A., Chuva De Sousa Lopes, S. M., Demeestere, I., Dwek, S., Frith, L., Lambertini, M., Maslin, C., Moura-Ramos, M., Nogueira, D., Rodriguez-Wallberg, K., & Vermeulen, N. (2020). ESHRE guideline: Female Fertility Preservation. Human Reproduction Open, 2020(4).