Uptake of prenatal diagnostic testing for retinoblastoma compared to other hereditary cancer syndromes in the Netherlands

Approximately 5% of all cancers are caused by a genetic predisposition, with the mode of inheritance being mainly autosomal dominant. In the past 30 years the genetic cause of many hereditary cancer syndromes has been unravelled. Knowledge of the genetic predisposition can aid early diagnosis and management of cancer for affected mutation carriers. For unaffected family members, presymptomatic DNA diagnosis of the disease-associated mutation may enable informed choices about cancer screening or risk reduction strategies, including preventive surgery. Cancer genetic testing, however, can also affect reproductive decisions of mutation carriers [1‐5]. Reproductive options for couples at risk of having a child with a cancer risk predisposition may be: refraining from having children or accepting the risk, adoption or gamete donation. Other options may include preimplantation genetic diagnosis (PGD) (i.e. in vitro fertilization, with genetic testing of 1 or 2 cells of the embryo and transfer of unaffected embryos to the uterus) and prenatal diagnostic testing for the deleterious cancer gene mutation with the option to terminate the pregnancy in the case of a carrier foetus. Prenatal diagnosis (PND) and PGD for hereditary cancer syndromes were described as early as 1988 and 1998, respectively [6, 7]. Legal aspects of these two techniques, and thus availability, differ across countries; e.g. in some countries PND followed by abortion is not allowed, whereas in other countries PGD is prohibited [8, 9]. Access to PND and/or PGD is also limited in some countries because they are not covered by health insurances [9]. Both in society and in medical literature, PND and PGD for hereditary cancer syndromes have led to ethical, social and legal discussions [10‐15]. Issues under debate are that many cancer-predisposing mutations have incomplete penetrance and that the onset of disease often does not occur until early adulthood. Furthermore, some argue that through the early detection of cancer or preventive surgery, the disease may be managed without a substantial effect on quality of life [15]. Arguments put forward in favour of offering PND and PGD are that preventive surgery may have a large impact on psychosocial well-being [16] and that families with hereditary cancer syndromes are burdened by their increased risk and deserve the same choices as families with other high-risk hereditary diseases [12, 17].

PND with the intention to terminate the pregnancy of an affected child is likely to reflect the perceived burden of the disease, i.e. future parents will only consider PND when they perceive the disease to be severe and wish to prevent their child from suffering [14]. In the Netherlands, PND for most hereditary cancers is offered as a reproductive option after extensive and careful consultation of the future parents with the clinical geneticist, a psychosocial worker and the gynaecologist [18, 19]. In several countries, PND for cancer syndromes has been performed, as listed in a review from 2006 [1]. However, most of the studies from this review are case descriptions, and papers on consecutive series on the uptake of PND for cancer are sparse.

We previously reported on reproductive decisions of couples at risk of having a child with retinoblastoma (Rb), a rare type of eye cancer in early childhood [3, 4]. Several couples who participated in these studies reported that they had chosen PND to prevent the birth of an affected child with Rb. The present study was conducted to determine how many families have used PND as a reproductive option for Rb since DNA diagnosis for Rb became available in the Netherlands in 1990. To put these data into perspective, we compared the use of PND for Rb to the uptake of PND for four other cancer syndromes with autosomal dominant inheritance.

Table 1 shows the five hereditary cancer syndromes, the number of mutation-positive families identified in the Netherlands, the total number of PNDs performed per cancer syndrome, and the number of couples that performed PND. PND was performed 35 times for Rb by 22 couples from 22 mutation-positive families (11.8% of 187 mutation-positive families). The percentages of families opting for PND for the other cancer syndromes ranged from <0.2% (HBOC) to 6.5% for VHL.

A significant difference in number of PNDs was seen between Rb and HBOC, and Rb and FAP. No differences were seen between PNDs for Rb and VHL and LFS.

In 14 out of 22 couples that used PND for Rb, one of the parents was a carrier of an RB1 mutation and the risk of a child with Rb was 50%. The other eight families concerned healthy parents with a child with a de novo RB1 mutation. The recurrence risk for these couples was 2–3%, based on possible germline mosaicism. For the other four cancer syndromes, the risk of an affected child was 50% for all cases. When confining the comparison analysis to Rb cases with a 50% risk, a significant difference in use of PND was still seen between Rb and FAP (p = 0.0011) and Rb and HBOC (p < 0.0001).

In this study, relatively large differences in the use of PND between cancer-predisposing syndromes were found. A significantly higher uptake for Rb than for the adult-onset cancer syndromes HBOC and FAP was seen. Uptake of PND did not differ significantly between Rb and two other early onset cancer syndromes VHL and LFS. PND for Rb started just 3 years after DNA diagnostic testing was introduced and uptake has been relatively stable over the years. PND for VHL, LFS, FAP and HBOC started 10–15 years after DNA testing was offered. A trend towards more PNDs for these syndromes after 2009 was noted.

The differences in uptake for PND observed in this study may be explained by several interdependent factors: differences in age of onset of cancer, disease penetrance, risk-reducing options and perceived disease burden, as noted by several authors in papers on PND or PGD for hereditary cancer [1, 5].

When age of onset is in adulthood, prospective parents may have the hope for better treatment options in the future for a carrier child, whereas in the case of childhood-onset the parents’ concerns will be more immediate. For adult-onset cancers, cancer diagnosis of an individual may not have been made until after family planning was completed. Rb is a high-penetrance disease of early childhood, and therefore parents of an affected child with Rb may still be in the reproductive age at the time of diagnosis of an affected child and may opt for PND in a subsequent pregnancy. Furthermore, physicians caring for patients with childhood cancer often have more intense contact with the family and will have more awareness of a possible impact of childhood cancer on family planning and be more knowledgeable about reproductive options than physicians caring for adult-onset cancer patients [31]. Differences in uptake may also be explained by the lack of risk-reducing options for the hereditary cancer syndromes with childhood-onset, apart from screening to detect cancer at an early stage [32]. For HBOC, mastectomy and prophylactic salpingo-oophorectomy can reduce cancer risk substantially, and the same applies to colectomy for FAP.

Lastly, previous studies on reproduction and hereditary cancer considered the perceived disease burden by individuals opting for assisted reproduction a factor of influence on uptake of PND [5]. For Rb, an extra disease burden follows from the intensive ophthalmological screening, which is done under anaesthesia in the first few years of life. Also, patients with heritable retinoblastoma have an increased risk for both a pineoblastoma (also referred to as trilateral retinoblastoma) and second tumours later in life and many have considerable late effects of treatment, e.g. an impaired vision or hearing loss. Perceived disease burden is not always related to a personal history of cancer, but can be shaped by many aspects, like caring for a family member with cancer [1, 5]. In our study of reproductive behaviour of individuals at risk of a child with Rb, the most important factor of influence on reproductive behaviour was perceived risk, not objective risk [4]. Both perceived disease burden and perceived risk may therefore be part of the reason eight parents with a child with a de novo RB1 mutation opted for PND, in spite of a recurrence risk of <3%.

One of the possible reasons PND uptake for Rb may differ from uptake for FAP and HBOC could be that diagnostic DNA testing of Rb started earlier than for FAP and HBOC. Therefore analysis comparing uptake for Rb to FAP and HBOC was done again, while taking into account the year DNA diagnostic testing became available. This analysis, however, did still show a significant difference between uptake for Rb and uptake for FAP and HBOC.

Observed higher uptake for Rb may be a reflection of differences in counselling between our clinical genetics department (with the highest number of counselees for Rb) and the other eight clinical genetics departments in the Netherlands. However, 13 PNDs and pre-PND counselling for Rb were performed elsewhere. Since there is a close collaboration between the nine clinical genetics departments in the Netherlands, policy towards counselling and PND is much the same.

PND for hereditary cancer has been reported in other countries, although in limited numbers, making it difficult to compare these data to our findings [1]. One paper on the clinical perspective on ethical arguments around PND and PGD for later-onset cancer syndromes from the Regional Genetics Service in Manchester mentioned one couple out of 110 families with FAP known in their centre that had undergone PND, and none from 356 HBOC families [14]. In Canada, PND for Rb is done to enhance early management of RB1 carrier infants and not with the option to terminate the pregnancy [33]. In the case of an affected child, premature delivery at 36 weeks’ gestation is recommended to be able to treat as early as possible.

One of the limitations of this study is that the number of mutation carriers in the reproductive age in each family was not known. However, since a relatively large number of families were included, we believe that our data on the uptake of PND in the cancer syndromes are by and large reliable. A trend towards increasing uptake of PND for hereditary cancers other than Rb after 2009 was observed. In 2008, PGD for hereditary cancer was temporarily restricted by the Dutch Minister of Health because of an ethical debate on PGD for diseases with a penetrance of <100%, such as HBOC [34]. Public debate in the media about hereditary cancer and reproduction during those years may have alerted at-risk couples to the option of both PGD and PND. Future research will have to determine whether the observed increasing trend of PND uptake over the past 5 years for VHL, LFS, FAP and HBOC will continue.

In conclusion, PND for Rb started many years before it was used for the other hereditary cancer syndromes. PND has been done significantly more often for Rb than for FAP and HBOC. Uptake of PND was not significantly different between Rb and VHL, and Rb and LFS. Early onset, high penetrance, lack of preventive surgery and perceived burden of disease may explain these differences. Knowledge regarding the underlying motives of couples that have opted for PND as a reproductive option is useful to improve care for families with a genetic predisposition for cancer.