Abstract

BACKGROUND

In May 2006, the UK Human Fertilization and Embryology Authority (HFEA) approved use of preimplantation genetic diagnosis (PGD) for lower penetrance, late onset cancer susceptibility syndromes such as hereditary breast and ovarian cancer (HBOC). This is the first report on views of BRCA gene mutation carriers on use of PGD for HBOC.

METHODS

Between December 2005 and February 2006, a postal survey of BRCA mutation carriers attending a Familial Cancer Clinic was undertaken.

RESULTS

Of 102 women sent questionnaires, 52 (51%) responded. Thirty-nine (75%) felt it was acceptable to offer PGD for HBOC. Fifteen (37.5%) of 40 who had completed their families would personally have considered PGD if it had been available. Only one of seven (14%) contemplating a future pregnancy would consider PGD. Eighteen (35%) wrote extensively about their concerns including increasing availability of effective treatment and good quality of life.

CONCLUSIONS

The majority of BRCA gene mutation carriers are supportive of offering PGD to others, thus endorsing the HFEA decision. However, most women would not consider it personally. Concerns raised highlight the need for regular HFEA reviews of the licensing criteria, as HBOC may cease to be a “serious life threatening illness” in the future.

Introduction

Preimplantation genetic diagnosis (PGD) involving in vitro fertilization (IVF) and embryo biopsy was developed to prevent pregnancies affected with serious life-threatening genetic diseases. It has been used for high penetrance recessive (cystic fibrosis, β-thalassaemia), dominant (Huntington's disease, myotonic dystrophy) and X-linked disorders (Fragile X, Duchenne muscular dystrophy) which occur early in life and for high penetrance cancer syndromes (familial adenomatous polyposis coli, multiple endocrine neoplasia) that occur later in life (Ao et al., 1998; Sermon et al., 2005; Harper et al., 2006).

Recently there has been a debate about extending use of PGD to include lower penetrance, late onset cancer susceptibility syndromes such as hereditary breast and ovarian cancer (HBOC) (Robertson, 2003). Regarding HBOC, women with BRCA gene mutations have a lifetime breast cancer risk of 65–85% (Antoniou et al., 2003). In addition the ovarian cancer risk is 18–56% for BRCA1 carriers and 14–27% for BRCA2 carriers (Sogaard et al., 2006). Cancers occur most commonly from the age of 40 and there is the possibility of risk reducing surgery, early detection and effective treatment. Acknowledging the inherent differences between these conditions and those previously licensed, the UK Human Fertilization and Embryology Authority (HFEA) undertook a public consultation between December 2005 and March 2006. The views of patients were highlighted as an important factor in reaching a decision. However only nine (8%) of 118 individuals present at the public consultation meeting and four (1%) of 283 respondents to a written HFEA questionnaire were patients or patient group representatives (HFEA, 2006b).

In May 2006, the HFEA decided that in principle it was appropriate for PGD to be available for HBOC. The first application for use of PGD in UK for BRCA gene mutation is about to be submitted to the HFEA by University College London Hospital (UCLH; personal communication). It is therefore timely to report on the views of BRCA carriers on PGD as a reproductive option.

Materials and Methods

The Familial Cancer Clinic at UCLH was set up in April 2004 for management of ovarian cancer risk in women at risk of familial ovarian cancer. All women (excluding those terminally ill) over 18 with a confirmed BRCA gene mutation who had attended the clinic were invited to participate in the study. Between December 2005 and February 2006, they were sent a patient information leaflet about PGD (process, advantages/disadvantages, alternative option of prenatal diagnosis/PND), study questionnaire and freepost envelope. The study was approved by the local research ethics committee.

The questionnaire collected relevant clinical information, plans for future pregnancies, concerns about transmission and views on pregnancy termination for: (i) unwanted pregnancy; (ii) serious genetic abnormalities (Down's syndrome, cystic fibrosis) and (iii) following PND for BRCA mutations. They were asked if they would personally consider PGD as a reproductive option, whether they approved of its use for other BRCA carriers and were questioned on factors related to the PGD technique (IVF, small risk of misdiagnosis, inconvenience) and affordability. There was a free text section for comments. Women were given the choice to remain anonymous. The women who identified themselves were contacted again to check test-retest validity.

The comments were typed and independently coded by three authors using constant comparison to identify themes and discussing cases to achieve a consensus (Mays and Pope, 1995; Pope et al., 2000).

Results

Questionnaires were sent to all 102 eligible women. Fifty-three completed questionnaires were returned. The eligibility of one woman could not be confirmed.

The baseline data on age, mutation status, personal history of breast cancer and parity was available for 93 of the 102 invited women. On these parameters, the respondents were broadly representative of those invited. The median age of invited women was 42 (range 29–72 years) versus 43 (range 30–69 years) in the respondents. The proportion with a personal history of breast cancer was similar (48% invited versus 50% respondents), as was the proportion of BRCA1 mutation carriers (61 invited versus 63% respondents) and parity (1.7 for both) (Table 1). Seventy-nine percent of respondents were aged over 35. In 81% the gene mutation was diagnosed at 35 or above.

Table 1:

Baseline characteristics of respondents

Characteristic Number of women, n = 52 (%) 
Marital status  
 Single 9 (17) 
 Married/in relationship 43 (83) 
Employment status  
 Employed 40 (77) 
 Not working 11 (21) 
 Missing information 1 (2) 
Considered themselves religious 23 (44) 
Religion in those who were religious (n = 23)  
 Jewish 4 (17) 
 Roman catholic 4 (17) 
 Church of England 5 (22) 
 Other Christian 3 (13) 
 Not stated 7 (31) 
Carrier status  
 BRCA 1 33 (63) 
 BRCA 2 18 (35) 
 BRCA 1 and 2 1 (1) 
 Not testeda 1 (1) 
Personal history of cancer 26 (50) 
 Relatives with breast cancer  
  0 1 (2) 
  1–3 35 (67) 
  ≥ 4 16 (31) 
Relatives with ovarian cancer  
 0 27 (52) 
 1 16 (31) 
 2 8 (15) 
 3 1 (2) 
History of cancer  
 Mother 30 (58) 
 Sister 5 (10) 
 Both 6 (11) 
Previous pregnancy loss  
 None 28 (54) 
 Ectopic 2 (4) 
 Miscarriage 14 (27) 
 Termination 8 (15) 
Parity  
  0 10 (19) 
  1 9 (17) 
  2 25 (48) 
 ≥ 3 8 (15) 
No information  
Characteristic Number of women, n = 52 (%) 
Marital status  
 Single 9 (17) 
 Married/in relationship 43 (83) 
Employment status  
 Employed 40 (77) 
 Not working 11 (21) 
 Missing information 1 (2) 
Considered themselves religious 23 (44) 
Religion in those who were religious (n = 23)  
 Jewish 4 (17) 
 Roman catholic 4 (17) 
 Church of England 5 (22) 
 Other Christian 3 (13) 
 Not stated 7 (31) 
Carrier status  
 BRCA 1 33 (63) 
 BRCA 2 18 (35) 
 BRCA 1 and 2 1 (1) 
 Not testeda 1 (1) 
Personal history of cancer 26 (50) 
 Relatives with breast cancer  
  0 1 (2) 
  1–3 35 (67) 
  ≥ 4 16 (31) 
Relatives with ovarian cancer  
 0 27 (52) 
 1 16 (31) 
 2 8 (15) 
 3 1 (2) 
History of cancer  
 Mother 30 (58) 
 Sister 5 (10) 
 Both 6 (11) 
Previous pregnancy loss  
 None 28 (54) 
 Ectopic 2 (4) 
 Miscarriage 14 (27) 
 Termination 8 (15) 
Parity  
  0 10 (19) 
  1 9 (17) 
  2 25 (48) 
 ≥ 3 8 (15) 
No information  

aHas a personal history of breast cancer age 27 years with a documented BRCA2 mutation in the family.

Thirty nine (75%) women felt it was acceptable to offer PGD for HBOC. Fifteen (37.5%) of 40 who had completed their families would personally have considered PGD if it had been available. Only one of seven (14%) contemplating a future pregnancy would consider it (Table 2). All women who would personally consider PGD were willing for others to be offered the procedure. The women's spontaneous free text comments were consistent with their questionnaire responses. The 17 women who would personally consider PGD tended to be somewhat different from those who would not consider it (Table 3). Numbers were too small for formal statistical comparisons.

Table 2:

Questionnaire responses — summary of women's attitudes towards PGD and PND for BRCA gene mutation and pregnancy terminations

Considering a future pregnancy No. of women Finds acceptable Would personally consider 
PGD offered to others with BRCA mutations Termination for serious genetic abnormality Termination for unwanted pregnancy PGD for BRCA mutation PND for BRCA mutation 
Yes 7 (100) 5 (71.4) 4 (57.1) 1 (13.4) 1 (13.4) 
Unsure 2 (40) 3 (60) 2 (40) 1 (20) 1 (20) 
No 40 30 (75) 31 (77.5) 22 (55) 15 (37.5) 5 (12.5) 
Overall 52 39 (77.6) 39 (75) 28 (53.8) 17 (32.6) 7 (15.3) 
Considering a future pregnancy No. of women Finds acceptable Would personally consider 
PGD offered to others with BRCA mutations Termination for serious genetic abnormality Termination for unwanted pregnancy PGD for BRCA mutation PND for BRCA mutation 
Yes 7 (100) 5 (71.4) 4 (57.1) 1 (13.4) 1 (13.4) 
Unsure 2 (40) 3 (60) 2 (40) 1 (20) 1 (20) 
No 40 30 (75) 31 (77.5) 22 (55) 15 (37.5) 5 (12.5) 
Overall 52 39 (77.6) 39 (75) 28 (53.8) 17 (32.6) 7 (15.3) 

Values are numbers (and percentages) unless otherwise stated.

Table 3:

Questionnaire baseline characteristics — comparision between women who would personally consider using PGD and those who would not or were unsure

Baseline issues PGD for BRCA carriers 
Would personally consider it n = 17 (%) Would not consider PGD n = 25 (%) Unsure n = 10 (%) 
Age, mean 37 48 35 
No. of children, mean 
Concerned about transmission to children 10 (59) 7 (28) 7 (70) 
Previous abortion 4 (24) 3 (12) 1 (10) 
Personal history of breast cancer 10 (59) 9 (36) 5 (50) 
In stable relationship/married 13 (76) 22 (88) 8 (80) 
Religious 5 (29) 13 (52) 5 (50) 
Considering future pregnancy 1 (<1) 4 (2) 2 (20) 
Employed 10 (59) 21 (84) 9 (90) 
Baseline issues PGD for BRCA carriers 
Would personally consider it n = 17 (%) Would not consider PGD n = 25 (%) Unsure n = 10 (%) 
Age, mean 37 48 35 
No. of children, mean 
Concerned about transmission to children 10 (59) 7 (28) 7 (70) 
Previous abortion 4 (24) 3 (12) 1 (10) 
Personal history of breast cancer 10 (59) 9 (36) 5 (50) 
In stable relationship/married 13 (76) 22 (88) 8 (80) 
Religious 5 (29) 13 (52) 5 (50) 
Considering future pregnancy 1 (<1) 4 (2) 2 (20) 
Employed 10 (59) 21 (84) 9 (90) 

It is not possible to perform tests of significance due to the small numbers.

The 23 women who identified themselves were contacted again to check test-retest validity. There was 93% agreement with plans for a future pregnancy and on whether PGD for BRCA mutations should be offered to others, and 80% agreement on whether they would personally consider it.

Eighteen women (35%) (two of whom might have considered PGD if they were younger and a further seven who stated they were supportive for others to have access to PGD) wrote extensively about their concerns on extending the boundaries for PGD to include HBOC (Table 4):

Table 4:

Summary of respondents free text comments (from 18 womena) expressing concern about offering PGD (embryo selection) as a reproductive option to BRCA carriers

Issues raised No. of women 
Lower penetrance 
Late onset 
Preventive surgery, early detection and effective treatment available 
Good quality of life despite cancerb 10 
Issues related to children 10 
Critical of science/genetics 
Carriers' value to society 
Anti selection/eugenics 
Pro life 
Increased risk of ovarian cancer due to IVF 
Issues raised No. of women 
Lower penetrance 
Late onset 
Preventive surgery, early detection and effective treatment available 
Good quality of life despite cancerb 10 
Issues related to children 10 
Critical of science/genetics 
Carriers' value to society 
Anti selection/eugenics 
Pro life 
Increased risk of ovarian cancer due to IVF 

aSeventeen of these women were also concerned about the PGD technique.

bSeven of the ten have personally had breast cancer.

‘How can you choose between [name A] and [name B] only because [name B] may have a high risk of developing cancer in her 30’s and 40's? Is her life less valuable? Is my life not considered worth living because I have to carry around the knowledge that any day I may be diagnosed with breast or ovarian cancer? Does this fact erase any of the value and fulfillment of my having a lovely family and 2 beautiful children (who may be BRCA carriers or not) and all the lives I have had the opportunity to touch by being me? I love my life and I am shocked to think that had my mother lived in another time she could have chosen to terminate her pregnancy and try again had she found out that I was a carrier!' (Patient 5).

‘I have had my ovaries removed and a history of breast cancer. However I do believe that PGD is unnecessary for women or men who carry BRCA1/2. It is very different for those illnesses whose certain outcome is disability or early death.’ (Patient 19).

‘BRCA2 is not a death sentence if a carrier is aware of it and takes steps to prevent the cancer or catch it at an early stage’ (Patient 8).

‘Of course I don't want my children to be carriers. I am very concerned about this. And I don't mean to minimize the heartache, stress and the harshness of the reality of living with this BRCA1 gene. But I cannot compare that to justifying ending a life before it starts because of this possibility and reality. I am appalled and very frightened to think that this is where science and genetics are leading us!’ (Patient 5).

Of the 17 (32.6%) women who were willing or would have considered PGD as a reproductive option, only 4 (23.6%) were willing to pay £3000–£7000 for the procedure. Seven were unsure. The only woman who intended to have a future pregnancy and would consider PGD commented:

‘I think it is imperative that funding is available for all BRCA carriers to go through PGD should they choose. We are a tiny proportion of the cancer community and face a terrific risk, emotional trauma. In the long term there is a clear saving: less patients needing expensive cancer care in the future’ (Patient 1).

With regard to the process, 28 women had concerns: 13 about undergoing IVF, 13 about the small risk of misdiagnosis, 5 about the low success rate and 5 about the inconvenience.

Discussion

This is the first report on views of women with BRCA gene mutations on PGD as a reproductive option for HBOC. Seventy-five percent agreed that PGD should be offered to others in these circumstances, providing endorsement by patients of the HFEA decision to extend PGD licensing. The fact that the data was collected prior to the authority's decision and ensuing publicity adds strength to its value.

However despite this general support, 35% of women (including women who were pro-PGD) raised concerns about broadening the regulatory guidelines to include HBOC. This group of women took time to write in extensive detail about their good quality of life, their value to society and the increasing availability of effective management and treatment strategies. They were well qualified to comment on the implications of being a carrier as 50% had been diagnosed with breast cancer and 79% had at least one close relative diagnosed with cancer. Their views highlight the need for regular HFEA review of the licensing criteria as HBOC may with the advancement of science cease to be classified as a ‘serious life-threatening illness’. Dame Suzi Leather, previous Chair of the HFEA acknowledged this when she stated that the Authority had agreed to license PGD for inherited breast, ovarian and bowel cancer because of the aggressive nature of the cancers and the extreme anxiety that gene carriers can experience. However they were aware that these conditions had very different impacts on individual families and the Authority would need to review all the factors around a particular condition including treatment options, and the views and experience of carriers (HFEA, 2006).

Patient acceptability will ultimately determine the value of this option. A total of 37.5% would have considered PGD if it had been available before they completed their families. However, only 14% of women considering a future pregnancy expressed personal interest in PGD. There is little comparable data about uptake of PGD in other diseases. In a study of parents of children affected by cystic fibrosis in the Netherlands, 14% of all parents planning to have more children stated they would consider using PGD (Henneman et al., 2001). Respondents who would personally opt for PGD tended to be younger, less religious, more likely to have had breast cancer and more concerned about passing the gene mutation to their children (Table 3). All were willing for others to be offered PGD reinforcing their views on PGD use.

More women would consider PGD than PND. This is in keeping with previous surveys where patients planning future pregnancies preferred PGD as only unaffected embryos are transferred, avoiding the need for a termination (Snowdon and Green, 1997; Lavery et al., 2002). The women have similar views to the general population on the acceptability of pregnancy termination for a serious genetic abnormality. In a general survey on legalization of PGD in Germany, 70% of respondents were in favour of PGD for Down's syndrome (Meister et al., 2005).

The UCLH clinic is one of the largest services in the UK providing risk management to women at high risk for familial ovarian cancer. The questionnaire was sent to all 102 women with BRCA gene mutations who had attended the clinic and were not terminally ill. The sample size is similar to other studies on PGD carried out from single centres. Lavery et al., (2002) surveyed 67 couples attending the Hammersmith Hospital on their attitudes to PGD. Such data is essential to inform larger surveys that require multicentre participation such as that by Snowden and Green (1997). The acceptability rate of 52% is similar to that reported in most published surveys on PGD—53% by Lavery et al., (2002) and 48% by Snowden and Green (1997). The women who agreed to take part in this survey appear to be representative of those invited on measures of age, mutation status, parity and breast cancer history.

The clinic population however is not representative of the wider sample of BRCA gene mutation carriers. The study cohort is limited to healthy women, breast cancer survivors and those currently in remission after treatment of non-ovarian cancer. Their better quality of life may have biased the perception of the cohort to the seriousness of being a carrier and hence decreased the number of pro-PGD respondents. Women with poor prognosis such as those terminally ill and those diagnosed with ovarian cancer, whose prognosis is worse than breast cancer, were not included (the former because it was perceived to be unethical and the latter as these patients are not referred to the recruiting clinic, where the focus is on managing ovarian cancer risk). However it should be noted that these women would never be able to personally avail themselves of PGD. It should also be noted that 48% of the sample had experience of ovarian cancer in one or more relatives and most had experience of a relative dying of cancer. Male carriers were also not included and their views as parents with affected or at risk children or potential new parents are important. In addition, the majority of the women were aged over 35. While an older more experienced cohort is better qualified to understand and comment on the complex issues related to life as a carrier, a younger population with more women who were considering future pregnancies would be more informative about PGD acceptability and uptake. Despite these limitations, the issues raised by the female gene carriers in this study are of relevance, as it is the first time they have been voiced in a formal study. As emphasized by the HFEA, when it comes to techniques such as PGD, the views and experience of each individual family is of particular importance (HFEA, 2006a).

In most women, the gene mutation was diagnosed after the age of 35. As risk management strategies for breast and ovarian cancer such as screening currently commence at the age of 35 (except in families with very early onset disease), there is little incentive to undertake mutation testing earlier. However with the licensing of PGD, the age of genetic testing in members of HBOC families who would like to opt for the procedure is likely to fall.

Many women independently commented about issues raised. While this was not part of a rigorous in-depth qualitative investigation, their responses provide important insights into attitudes to PGD and highlight the need for more extensive qualitative research and larger multicentre surveys to gain a better understanding of this complex field.

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