This is the first large-scale quantitative study to report a variety of attitudes toward genetic testing, family planning, and PGT in families affected by the CDKN2A PV.

An increasing number of families affected by a CDKN2A PV have been identified over the past two decades. In the current study, most confirmed carriers became aware of their potential carrier status after they had children (median age of 36 years) and subsequently underwent genetic testing after the age of 40. By then, confirmed carriers were eligible to participate in pancreatic cancer surveillance, which was reported to be an important motivation for seeking genetic testing. In addition, the skin surveillance interval was shortened to every six months following confirmation of CDKN2A PV. Both skin and pancreatic cancer surveillance programs have been shown to detect tumors at more favorable prognostic stages, leading to improved survival outcomes [1, 3, 12, 13].

Other important motivations for genetic testing were the desire to gain knowledge about their own and children’s cancer risk. These motivations were in line with a previous cohort study of Australian family members with hereditary melanoma due to a CDKN2A PV [14]. However, while 67% of the at-risk carriers in this Australian cohort were willing to undergo genetic testing, only 21% ultimately did so. This low testing rate may be due to the understanding that a negative test result did not eliminate the importance of skin protection and skin self-examination. Moreover, there was little evidence of an elevated lifetime risk of pancreatic cancer within these Australian families, potentially further diminishing the necessity for genetic testing. Although the specific CDKN2A PV was not disclosed in this Australian study, most PVs described in the literature affect the p16INK4a protein, generally correlating with a 15–20% lifetime risk of pancreatic cancer [15].

In our study cohort, the association between the p16-Leiden variant and pancreatic cancer has been well established [1, 16]. Nearly half (46%) of at-risk carriers had a positive attitude towards genetic testing, generally driven by a desire to learn more about their personal cancer risk and to improve cancer screening practices. However, considering that the typical age of onset of pancreatic cancer in this population is around 55 years, and pancreatic cancer surveillance requires a minimum age of 40 years, it is plausible that at-risk carriers may postpone genetic testing until they reach this surveillance age threshold [17]. Interestingly, a contrasting perspective was expressed by confirmed carriers, with the majority recommending earlier testing (18–35 years) for their children. This age preference for testing was motivated by a desire to equip their children with the knowledge necessary to make autonomous decisions about genetic testing, family planning and potential financial implications of a positive test result. Our previous focus group study found that most at-risk carriers primarily rely on information and experiences shared by family members, with limited use of formal genetic counselling from a clinical geneticist [6]. Approximately half of the at-risk carriers in the current study showed hesitancy or reluctance toward genetic testing and expressed concern about the financial consequences of a positive test result, particularly with regard to obtaining a mortgage and life insurance. However, in the Netherlands, life insurance is not mandatory for obtaining a mortgage, and questions about hereditary cancer predisposition for life insurance are limited below €328,131 (legal question limit as of July 1, 2023) [18, 19]. Moreover, insurance companies often use even higher thresholds, implying that a positive genetic test may have less financial impact than perceived, as confirmed carriers generally qualify for standard disability or life insurance coverage under normal terms and conditions. However, it should be noted that the financial implications can be different for individuals with a personal history of cancer or if the insured amount exceeds this legal limit. Genetic counseling offers a tailored approach to these complexities, and we encourage at-risk carriers to seek such advice.

The vast majority of confirmed carriers (88%) made their family planning decisions independently of their hereditary cancer predisposition, either because they were unaware of their family’s genetic risk or because they had not yet undergone genetic testing at the time of starting a family. Some participants expressed a sense of relief in not knowing their genetic risk, and thus avoiding the burden of contemplating family planning decisions [6]. Interestingly, among at-risk carriers, all of whom were aware of their PV carrier status, three-quarters reported that this knowledge did not affect their family planning decisions. This consideration was primarily motivated by the belief that a positive PV carrier status does not necessarily translate into serious health consequences. This was supported by previous results from a Norwegian cohort study of families with a CDKN2A PV [20]. The Norwegian study identified seven distinct CDKN2A PVs across 18 different families, all of which were associated with a high risk of melanoma and a potential risk of pancreatic cancer. However, the uptake of genetic counseling and testing was relatively low compared with a similar cohort of BRCA1 families. This discrepancy may be explained by differences in perceived disease severity, as most CDKN2A PV carriers had survived melanoma, in contrast to the BRCA1 cohort, where a large percentage of affected relatives in the BRCA1 cohort had died of their disease [21]. Other previous qualitative studies of hereditary breast and ovarian cancer (HBOC) identified the familial domain as an important area of concern. Carriers expressed concerns about their children’s genetic status, fearing that their children may face similar issues, including cancer diagnoses, witnessing family loss, or encountering difficulties in finding a partner or making reproductive decisions [22,23,24,25].

PGT presents a potential option for individuals with a confirmed CDKN2A PV with concerns regarding family planning. This reproductive-assisted method facilitates the selection of embryos without the hereditary cancer predisposition, offering confirmed carriers the opportunity to have a genetically-related unaffected child while avoiding pregnancy termination. Our study showed that although the majority of confirmed carriers had already had a fulfilled desire to have children before genetic testing, only 19% expressed that, upon reflection, they would have considered PGT as a reproductive option. Among at-risk carriers, the positive attitude toward PGT was remarkably low (10%), given that two-thirds of them intended to have children. This is in contrast to a condition such as FAP, where childhood-onset disease necessitates invasive surveillance from the age of 12 and early prophylactic colectomy between the ages of 15 and 25 [26, 27]. By comparison, effective and relatively non-invasive cancer surveillance programs are available to CDKN2A PV carriers [1, 3, 5]. As a result, the use of PGT may be less urgent for CDKN2A PV carriers compared to individuals with hereditary cancer syndromes that involve burdensome preventive measures and surveillance methods and. However, it is noteworthy that even in FAP, only 30% of patients expressed a positive attitude toward PGT. This suggests that factors other than disease severity and surveillance practices contribute to PGT attitudes [8]. Studies of other hereditary cancer syndromes such as PJS, von Hippel-Lindau syndrome (VHL), and Li-Fraumeni syndrome (LFS) found that 35–52% of the individuals expressed a positive attitude toward PGT [7, 8, 11].

Furthermore, two-thirds of participants had never heard or did not recall having been told about PGT before the study. While the provided information in this study might have offered a basic understanding, it was likely insufficient to form a well-informed opinion about PGT. This aligns with findings from previous studies on HBOC couples [23, 29]. In one study, over 40% of participants reported difficulty making reproductive decisions, and 70% expressed a need for additional support [23]. Similarly, another study found that, despite 77% of participants receiving genetic counseling in which reproductive options were discussed, most couples (85%) were not equipped to make an informed choice about their preferred reproductive options, including PGT [29].

A strength of this study is the large sample size of confirmed CDKN2A PV carriers, which allows for in-depth exploration of their attitudes on important issues. However, the sample size of at-risk carriers was relatively small. In our study, the proportion of at-risk carriers was 16% (39 of 247 participants), which is comparable to the proportion of 13% in similar studies of other rare hereditary cancer syndromes, including FAP, LFS, and VHL [8, 11]. In addition, previous literature has reported lower response rates in younger adults (aged 20–30 years) and males, which is consistent with our study [30].

As a result of the low response rate (23%) among at-risk carriers, non-response bias may have been introduced [31]. While demographic characteristics such as age and sex were comparable between participants and non-participants, the extent to which the cohort of respondents represents the overall population of at-risk carriers remains uncertain.

Furthermore, our study only focused on the perspectives of confirmed and at-risk carriers. To gain a more comprehensive understanding of reproductive decision-making, including PGT, it would be valuable to also consider partners’ perspectives. Previous research with FAP patients and their partners has shown that while about two-thirds of couples have similar attitudes toward PGT, there can be discrepancies. In cases of disagreement, partners often have a more positive view of PGT (56%). Hence, including partner attitudes may provide a more nuanced insight into reproductive decision-making within couples affected by the CDKN2A PV.

Lastly, the generalizability of our findings may be limited by our homogenous study population. All participants were Dutch and participated in the LUMC’s cancer surveillance programs. Cultural attitudes and regulations regarding (prenatal) genetic testing, mortgages, and insurance can vary significantly across countries. Therefore, these findings might not be directly applicable to other international hereditary cancer cohorts.