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Valorisation addendum

Introduction

To ensure that one reflects on the potential effects of its research it is important to critically evaluate the impact on science and society as a whole. This addendum discusses the valorization potential of the main topics of this thesis: oncological and fertility aspects in treatment of early stage breast cancer in young women.

Case

Judy is 25 years old, has a male partner and has just started living together after she has completed her study. Just a few months after she started with the job of her life, she discovers a mass in her breast. The next few days feel like a rollercoaster. She is diagnosed with early stage breast cancer and therefore needs to undergo a breast MRI (multi resonance imaging), has to make a decision on the type of operation, receives information regarding chemotherapy and endocrine therapy and has to decide upon genetic testing. Due to the possible negative effect of chemotherapy on ovarian reserve, she also has to think if at a certain point in her live she wants to have children.

Relevance of the findings

Breast cancer is the most frequently diagnosed malignancy in women, with approximately 12% being younger than 40 years of age. Young women confronted with breast cancer have to face an added burden of unique concerns. Breast cancer in young women is of major importance because of an increased risk of recurrence, both local and systemic, and increased risk of death as compared to breast cancer in older patients. Over the past years, the mortality of early stage breast cancer has decreased. This is the result of earlier detection, multidisciplinary approach and improved systemic therapies. However, due to its high incidence and mortality risk, a diagnosis of breast cancer at young age has a huge personal, societal and economic impact.

In breast cancer patients treated with neoadjuvant chemotherapy, the sequentially delivered AC‐T (docetaxel after anthracyclines and cyclophosphamide) chemotherapy showed a better survival as compared to the concurrent triplet TAC (docetaxel, anthracycline and cyclophosphamide) chemotherapy. The results from our Dutch INTENS study have been used in a global meta‐analysis, strengthening our own observations. The Dutch national guideline on breast cancer, updated in 2018, refers to the results of this trial. The improved outcome is important information for patients and has been practice‐changing.

MRI use in breast cancer patients treated with neoadjuvant (i.e. before the operation) chemotherapy was associated with a reduced number of mastectomies as first surgical procedure, particularly in patients with large invasive ductal breast tumors. This reduction was not seen in lobular cancer. These research findings are important for women with early stage ductal breast cancer treated with neoadjuvant chemotherapy: when they have undergone breast MRI, they have a higher chance of being eligible for breast‐sparing treatment. When they have lobular breast cancer, breast MRI may not give additional information influencing the type of surgery and does not need to be performed for that reason. This may lead to a better, cost‐effective resource use, which is important at a societal level to control healthcare costs.

When administering chemotherapy and endocrine therapy, the menopausal status of the women has to be taken into account. Chemotherapy is known to negatively influence the ovarian function. Ovarian function suppression is beneficial for patients with hormone‐receptor positive breast cancer in terms of overall survival. We have shown that rather a high rate of patients (12%) with chemotherapy‐induced ovarian function failure aged 45 years and beyond, who received adjuvant anastrozole after two to three years of adjuvant tamoxifen (both endocrine therapies), experienced recovery of ovarian function during anastrozole therapy. Noteworthy, these women had an increased risk of breast cancer recurrence as compared to those who did not have an ovarian function recovery. The efficacy of the adjuvant endocrine treatment with aromatase inhibitors is diminished as a result of the recovery of ovarian function, and in fact may result in rather high estrogen levels. The Dutch national guideline on breast cancer, updated in 2018, refers to the results from this trial. Therefore, the current recommendation is not to prescribe aromatase inhibitors as adjuvant endocrine therapy to women with chemotherapy‐induced ovarian function failure, irrespective of their age at diagnosis, when not treated in addition by LHRH agonist or by bilateral adnexextirpation.

Whereas ovarian function suppression is beneficial for the overall survival of patients with hormone‐receptor positive breast cancer, permanent ovarian function suppression in women with an unfulfilled family planning has a negative impact on their quality of life. We have shown in this thesis that in the majority of young women, ovarian function recovered after chemotherapy‐induced ovarian function failure in the months – few years thereafter. Shortly after the end of chemotherapy in nearly all ovarian function was suppressed. Two years after chemotherapy, chemotherapy‐induced ovarian function failure was present in only 9% of women treated with chemotherapy at an age below 40 years. This is reassuring for the young women with a future desire to have offspring. These data are now used in the counseling of new patients when deciding on undergoing a fertility preservation procedure before chemotherapy, or not.

Fertility preservation procedures before the start of chemotherapy can enhance the chance of fulfilling the desire to have biologic offspring in the future. Up to now, only few data were available about the women choosing for fertility preservation and the uptake of the cryopreserved eggs and embryos. And also, limited data were available on the chance of resumption of menses and the potential to get pregnant after chemotherapy induced ovarian function failure. We have shown that after counseling, twenty‐nine percent of young women with an early stage breast cancer (total n=118) elected fertility preservation by cryopreservation of embryos or oocytes. After a median follow‐up of over 4 years, only three of the 34 couples used their frozen embryos in an attempt to achieve a pregnancy. Interestingly, all three had a recovery of ovarian function, and two of these actually used the embryo’s for preimplantation genetic diagnosis (PGD) because of a BRCAN‐mutation carriership. In the total group, twenty‐six mothers gave birth to thirty‐two babies. The 5‐year live birth rate was 27%. This high percentage is reassuring for the young women with breast cancer and also important for the medical team to bear in mind when discussing the risk of reduced future fertility related to the oncological treatment. Referral for fertility preservation counseling is a critical service and should be discussed with all appropriate young patients with a breast cancer diagnosis. There are varying reasons why patients may not choose to proceed with fertility preservation, but the discussion is still useful. Patients may be concerned about the time delay built in the process of fertility preservation or the risk of hormone use during the fertility preservation procedure or later pregnancy. Fortunately, our study points out that there does not appear to be an unfavorable impact on outcomes. The fact that most of these young women had return of ovarian function and did not use their cryopreserved oocytes or embryos is a very reassuring finding. It does suggest that we may be able to better define the populations of patients who may be more versus less likely to benefit from fertility preservation, primarily based on age. On the other hand, even the very young are faced with a small risk of permanent ovarian function failure and may wish to choose a fertility preservation procedure.

Target group, implementation activities and products

The information in this thesis has improved the oncological therapy of women with early‐stage breast cancer (choice of chemotherapy schedule, type of breast surgery related to MRI scanning), and improved the counseling of young women with an incomplete family planning at breast cancer diagnosis by increased insight on the risk of permanent ovarian function failure. We have discussed the results of our studies with our partners in the affiliated hospitals in the OncoZON‐region (Oncologisch netwerk Zuid‐Oost Nederland). Moreover, in the national guideline on breast cancer, updated recommendations are implemented based on the results of our trials.

The results of the studies reported in this thesis have been presented at international (breast) cancer symposia. More specifically, results were presented at the annual San Antonio Breast Cancer Conference (SABCS) in San Antonio, Texas, USA as a poster presentation (2014) and in a poster discussion session (2016), at the European Breast Cancer Conference (EBCC) by an oral presentation and a poster in the spotlight session (Amsterdam, 2016) and at the conference of the American Society of Clinical Oncology (ASCO) in Chicago, Illinois, USA by a poster presentation (2017). As a result of these presentations, a lot of attention was paid to this topic in the media, interviews for magazines were given and a video was made (https://www.medtalks.nl/sabcs‐2016‐jonge‐vrouwen‐met‐borstkanker).

Conclusion

The studies presented in this thesis provide essential data on several aspects of diagnosis and treatment of early‐stage breast cancer. These data already contribute to an improved prospect of (young) women recently diagnosed with early‐stage breast cancer worldwide.