Articles that met the inclusion criteria were evaluated, and data from these articles were extracted (BM). The included articles were checked by a second reviewer to determine if they met the inclusion criteria (KT). The literature search identified 309 references as potentially relevant. After reviewing these, 22 references were selected for detailed review (Table 1).

Breast conserving surgery (followed by radiotherapy) is the treatment of choice for many women diagnosed with an early breast cancer. Most women with early breast cancer are cured from their disease 7, and evidence suggests there is no difference in mortality at 10 years between BRCA mutation carriers and non-carriers 11. However, in women who carry a BRCA mutation, the risk of a recurrence or a new primary in the ipsilateral breast at 10 years is estimated to be as high as 20% to 50% 12. The risk at 10 years for a contralateral second primary cancer is approximately 30% and is modestly greater for women diagnosed before age 50 years 1314. There is good evidence that contralateral risk-reducing mastectomy decreases the risk of breast cancer by up to 95% 1516171819. Therefore, as survival from early breast cancer continues to improve, consideration of the risk of developing a new primary breast cancer becomes more important if it impacts on the surgical management of the current cancer.

While the discussion so far has focused on known BRCA mutation carriers, it is important to emphasise that simply relying on the presence or absence of a BRCA mutation after a genetic test is an inadequate assessment of a woman's likely future cancer risks. A woman with breast cancer in whom a BRCA mutation has not been detected with current techniques may still have a significant risk of developing a new primary cancer depending on her associated family history, which, in turn, could still influence her decision regarding breast conserving surgery. Genetic counselling is an essential component of the genetic risk assessment in order to interpret the implications of a genetic test result, particularly if no mutation can be identified – an 'uninformative' result. The clinical implications of an uninformative result depend on whether or not a woman has a relevant family history of breast and/or ovarian cancer. Specifically, in a woman with a strong family history of breast and/or ovarian cancer, there is no convincing evidence that in the absence of a detectable mutation there is a substantial reduction in the chance of ipsilateral and/or contralateral breast cancer. There is some evidence that the risk of a second primary remains elevated in BRCA1 and BRCA2 mutation negative families, especially if the breast cancer was diagnosed early 20. Thus, women with a relevant family history of breast and/or ovarian cancer who receive uninformative results may still reasonably consider risk-reducing surgery on the basis of their strong family history alone. It is important that the information is discussed with genetic specialists to ensure correct interpretation of results, but also that these specialists understand that absence of a detectable mutation does not preclude a substantial risk of a further primary.

In other circumstances, specific personal and family features may mean that an uninformative test may support an assessment that it is less likely there is a hereditary syndrome, thus reducing estimates of risks for a new ipsilateral or contra-lateral breast cancer. In this instance, the woman can make an informed decision and reasonably elect breast conservation.

It is possible that a significant proportion of women found to have a deleterious mutation would opt for bilateral mastectomy if they had access to this information at diagnosis 2122232425. If a woman is identified as a BRCA mutation carrier, the mutation status can be used as a variable in the complex decision-making process regarding the use of radiotherapy and the type of surgery. The option of combining definitive and risk-reducing surgery as a unilateral or bilateral mastectomy after adjuvant therapy is completed avoids the need for additional surgery if a woman would have elected risk-reducing surgery at a later date following delayed genetic counselling with or without genetic testing 26. Furthermore, radiation treatment, which may negatively impact on the cosmetic outcome of breast reconstructive surgery, may be able to be avoided.

The discussion so far has focused on the relative roles of breast conservation versus mastectomy, so it could be argued that treatment-focused genetic counselling and testing need not be considered at this vulnerable time if women do not want to consider a mastectomy. However, we would argue that although a woman may not want to consider a mastectomy as her first reaction to a new cancer diagnosis, if she has a suspicious family history and does not have the opportunity for a full consultation about the possible associated cancer risks, she risks not being fully informed about the pros and cons for all the treatment choices available.

Women newly diagnosed with breast cancer with a BRCA mutation may also consider a risk-reducing salpingo-oophorectomy (RRSO) to reduce their significant associated future ovarian cancer risk 27. RRSO has been shown to reduce the risk of ovarian cancer by between 85% 28 and 95% 29. It also reduces the risk of subsequent breast cancer by up to 50% in BRCA1 and BRCA2 mutation carriers 28293031, with risk reduction being greatest for premenopausal women.

Although the cancer prevention considerations are important, the main indication for considering such surgery around the time of cancer diagnosis is because an oophorectomy is also an effective adjuvant treatment for oestrogen-receptor (ER) positive premenopausal breast cancer. Furthermore, RRSO will also permit the use of adjuvant aromatase inhibitors, which are superior to tamoxifen but are only effective in postmenopausal women 3233

There are emerging data that indicate that complete cellular loss of BRCA1 or BRCA2 function in BRCA-associated cancers confers increased resistance to agents such as taxanes 34, and that these tumours are more sensitive to DNA-damaging agents such as platinum agents 35. It is reasonable, therefore, to speculate that the known or likely BRCA mutation status of a woman could influence systemic therapy decisions and choice of chemotherapy once we have more definitive data from randomised trials. Moreover, further refining of pathological techniques may allow treatment targeted at aberrant molecular pathways of the tumour, which may be related to both somatic and germline BRCA mutations as well as other predictive markers. There is evidence that BRCA1-associated breast cancers are more aggressive 3637, and that adjuvant chemotherapy should be considered in the majority of mutation positive women, even those with small, node negative breast cancers.

As well as improvements in the understanding of the relative efficacies of conventional chemotherapy agents in the adjuvant treatment of BRCA1 or BRCA2 mutation carriers, novel agents such as PARP inhibitors have been developed that exploit the effect of a mutated gene in the associated cancers. The BRCA1 and BRCA2 genes are important for DNA double-strand break repair by homologous recombination. PARP is an enzyme involved in base excision repair, a key pathway in the repair of DNA single-strand breaks 38. The inhibition of PARP results in the development of DNA double-strand breaks that are normally repaired through the homologous recombination pathway mediated by BRCA1 and BRCA2. The BRCA1 or BRCA2 dysfunction occurring in cancers arising in BRCA1 or BRCA2 germline mutation carriers sensitises tumour cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and apoptosis, as these cells have no functioning copy of the BRCA genes. The other body cells are relatively insensitive to the effects of PARP inhibition as these cells still retain a functioning BRCA1 or BRCA2 gene. Consequently, the use of PARP inhibitors in BRCA-associated cancer has the potential for a wide therapeutic index between the effects of PARP inhibition on tumour and normal body cells 39.

Clinical trials using PARP inhibitors are underway in BRCA-associated cancers 40. If successful, and if they progress into the adjuvant arena, the use of PARP inhibitor agents will increase the need to ascertain a patient's BRCA mutation status around the time of cancer diagnosis. The results of phase 1 and 2 studies show that PARP inhibitors are very active agents 41, and it is likely that they will be investigated in the adjuvant setting for women with early stage breast cancer within the next few years.

There is a growing awareness of the potential benefits of understanding a woman's likely hereditary cancer risk status for the consideration of simultaneous therapeutic and contralateral risk-reducing mastectomy, better tailoring of conventional adjuvant therapies and the testing of novel agents in the adjuvant setting. There is a small window of opportunity to establish the optimal ways in which to offer treatment-focused genetic counselling and testing and to develop appropriate associated clinical pathways, in advance of a more widespread clinical demand.

The development of educational resources that support women considering genetic counselling and testing to make informed decisions as well as facilitating discussions between women and their health professionals is also critical. These resources will need to provide information for women to consider the potential advantages and disadvantages of this process. These include the added stress of undergoing genetic testing for a hereditary predisposition around the time of a breast cancer diagnosis; the implications of uninformative genetic test results; the possibility of delaying surgery for a short time while waiting for genetic testing results if there is no planned delay in definitive surgery or radiotherapy due to neoadjuvant or adjuvant chemotherapy; and the implications of this information for the wider family.

Raising the issue about the hereditary aspects of breast cancer at the time of diagnosis involves more than considering the usual pros and cons of genetic testing and, if a mutation is found, discussing the role of mastectomy as a risk-reducing strategy at some time in the future. It adds another layer of complexity to the decisions around cancer treatment when providing women with the opportunity to consider the wider issues that may affect their future survival and possible disease course rather than using the tumour staging and characteristics alone. There are a variety of management options, and this is complex information to convey at a vulnerable time, so this will require multi-disciplinary input from breast surgeons, plastic surgeons, medical and radiation oncologists as well as other health professionals involved in the care of women with breast cancer outside traditional genetic counselling services. Involvement of genetic specialists in the multidisciplinary team will ensure that these issues are brought up, but also that patients are not disadvantaged by ill informed application of these genetic tests. As genetic testing becomes faster and cheaper, some clinicians might believe that testing results indicate a clear set of treatment options. It is, however, essential that the decisions that arise as a result of genetic testing be considered within the context of the priorities of treating the current cancer. Integration of a new model of genetic counselling and testing to help direct therapy may also challenge assumptions that women who are coping with a recent diagnosis of breast cancer, and are already making multiple decisions about their treatment are not interested in, or able to cope with, additional information about their genetic risk.

There is strong evidence that the frequency of mutations in BRCA1 or BRCA2 genes is increased in women with a strong family history of breast and/or ovarian cancer involving multiple generations of affected blood relatives and/or those with a specific ethnicity or from certain geographical locations that are associated with known founder mutations. For example, Malone and colleagues 44 provide a summary of the literature and report that in women with extensive family histories, estimates of mutation frequency range from 20% to 50%. There is a consensus that women with strong family histories of breast and/or ovarian cancer should be offered genetic counselling and testing for mutations in the two BRCA genes (for example, National Breast Cancer Centre 45 and American Society of Clinical Oncology 146).

However, it is also clear that many mutation carriers will be missed if the presence of a strong family history of breast cancer and/or ovarian cancer is used as the sole criterion to offer genetic testing. Table 1 provides a summary of published studies on women with early onset breast cancer who have had genetic testing for BRCA1 and BRCA2 mutations; it shows that the proportion of women with a BRCA1 or BRCA2 mutation with no family history of breast/ovarian cancer ranges from 6% 47 to 78% 48. The lack of a family history of breast and/or ovarian cancer can arise because of a small family size, few female relatives of an age to have developed cancer, patrilineal inheritance, low cancer penetrance and non-disclosure of relevant family cancer diagnoses due to geographic or social distance between relatives 4249.

Table 1 also shows that the proportion of women found to have mutations in BRCA1 or BRCA2 genes varies considerably between studies, ranging from 2.0% to 33.0%. This variability is likely to be the result of differing populations, age selection criteria and mutation detection methods utilised. Studies vary in the extent to which they include women from ethnic backgrounds characterised by the presence of founder mutations, which will have specific population frequencies not applicable to a wider outbred population. The age selection criteria chosen for different studies also vary between under 31 to under 55 years. Finally, the diagnostic sensitivity of the methods used for the detection of BRCA1 and BRCA2 mutations varies 50. Accordingly, in Table 1 the studies are ranked for sensitivity of the mutation detection method. Sensitivity estimates are based on published data only and do not take into account the operator dependence of these methodologies.

Extracting the data for women aged under 40 years from the studies in Table 1 gives a BRCA mutation detection rate of between 4.9% 51 and 23.0% 52. A prior probability of mutation detection exceeding 10% 1 is generally considered sufficiently high to justify genetic testing for BRCA mutations through many public genetics clinics. It should be noted though that this threshold is not based on health economic analyses, and the cut-off to be used will depend on local availability of resources and ethnic mix.

There is an expanding body of literature about the psychological impact of genetic testing in affected women at increased risk for hereditary breast/ovarian cancer who were offered 'standard' genetic testing for BRCA1 and/or BRCA2 mutations, that is, genetic testing offered in the context of genetic counselling following completion of cancer treatment, as opposed to treatment-focused genetic counselling and testing (see Schlich-Bakker and colleagues 60 and Meiser 61 for reviews). This literature indicates that the impact of genetic testing is mediated and amplified by women's former experience of cancer 61. Women with a previous diagnosis of cancer have been found to be significantly more distressed compared to unaffected women following genetic testing 62 independently of carrier status 63. Women for whom the gap between being diagnosed with cancer and being genetically tested was less than a year tend to report greater reductions in well-being compared to those for whom the gap was longer 6465. This may indicate that genetic testing around the time of diagnosis may place additional psychological stressors on women or that women feel frustrated if they realise they might have selected an alternative therapy had they received genetic counselling prior to completion of cancer treatment. These results do not suggest that treatment-focused genetic testing should not occur, but rather that it should be provided in a supportive environment that is responsive to these wider issues.

Limited empirical data have been published that describe women's decision-making about, and the psychological and behavioural impact of, treatment-focused genetic testing in the context of a new diagnosis of breast cancer. In a key US study, Schwartz and colleagues 21266667 evaluated the impact on surgical decision-making in 194 newly diagnosed breast cancer patients who were offered testing before definitive surgery. In this study, women with a 10% prior probability of carrying a BRCA1 or BRCA2 mutation were offered genetic testing, and test results were made available within 2 to 3 weeks. Seventy-six percent of the study participants chose to have BRCA1 and/or BRCA2 testing; the decision to undergo testing was associated with physician recommendation and indecision about definitive local treatment 21. Twenty-one percent of the women who were tested proceeded with definitive local treatment before receiving their tests results; delays in the availability of test results and low levels of anxiety were associated with the decision to proceed with definitive local treatment 21. Schwartz and colleagues 21 also found that 48% of women who were found to carry a BRCA1 or BRCA2 mutation opted for bilateral mastectomy, compared to 4% of women who declined genetic testing. These findings indicate that knowledge of a BRCA1 or BRCA2 mutation before definitive surgery significantly increases the number of women opting for bilateral mastectomy for both treatment and risk reduction 266667. They also suggest that the presentation of the information about genetic testing by the treating clinician is an important factor in the final decision to undertake genetic testing.

The study by Schwartz and colleagues 26 also found that, compared with women who chose breast conservation or unilateral mastectomy, those who chose mastectomy of the affected breast and contralateral risk-reducing mastectomy of the unaffected breast did not report diminished quality of life or decreased distress 67. These results are consistent with findings from another study of 435 BRCA1 or BRCA2 carriers that assessed predictors and outcomes of the decision to undergo contralateral risk-reducing mastectomy and found no impact on distress outcomes of contralateral risk-reducing mastectomy 66. In this latter study the decision to undergo contralateral risk-reducing mastectomy (in conjunction with mastectomy of the affected breast) following treatment-focused genetic testing was associated with an informative, mutation positive test result, higher cancer-specific distress at baseline and younger age at diagnosis 66. Similarly, in an international cohort of women, uptake of contralateral mastectomy was found to be associated with younger age 68.

In the study by Schwartz and colleagues 2666 women opted into the study and received extensive pre- and post-test genetic counselling; the select nature of the sample and the unique resources of the study limit the generalisability of the results to other settings 69. Although the data reported by Schwartz and colleagues suggest few adverse psychological effects of treatment-focused genetic testing, further controlled studies in a range of different clinical settings are needed to determine definitively the psychological and behavioural impact of treatment-focused genetic testing for BRCA1 and/or BRCA2 mutations.

In another prospective study from The Netherlands, Schlich-Bakker and colleagues 607071 assessed predictors of the decision to undergo treatment-focused testing and its psychological impact in women with breast cancer who were about to commence adjuvant radiotherapy. The psychological distress levels of 102 women who met referral criteria for genetic counselling and testing were compared to those of 182 women who did not meet such criteria. The authors report that psychological distress levels did not increase after an active approach for genetic counselling and testing 6070. Of importance in this setting, not having a family history of breast cancer was found to predict long-term distress in the combined group of tested and untested women 6070. Of note, of the 102 patients who met referral criteria, only 57% opted to have genetic testing 71. Sixty-four percent of the 102 women were happy with the timing of genetic testing, while 13% would have preferred an earlier, and 19% a later, approach 71.

A small UK study by Arden-Jones and colleagues 72 explored whether women wanted to be offered information about genetic testing close to the time of diagnosis. Thirteen women, who were ascertained through a family cancer service, were under the age of 40 and were subsequently identified as BRCA1 or BRCA2 mutation carriers, participated in focus groups. The majority of women expressed the view that offering genetic testing around the time of a breast cancer diagnosis might add too much stress at a time when women were confronted with multiple demands on their coping abilities. However, some women supported testing around the time of breast cancer diagnosis if it could alter treatment decisions. All agreed that there was no 'right' time for everyone, with women expressing a preference for being told that the information was available if they wanted it rather than then being offered the test at the time of their cancer diagnosis. However, a broad range of views was observed and indeed some women said they would prefer to be tested immediately following their breast cancer diagnosis.

The study by Arden-Jones and colleagues 72 also found that health professionals involved in breast cancer care expressed concerns about informational and emotional overload caused by offering genetic testing at the time of a breast cancer diagnosis. Similar views were expressed in a recent study of 34 Australian cancer genetics practitioners that was undertaken to identify problematic or ethically contentious issues in cancer genetics consultations 73. The latter study also highlights: the rights of women to be fully informed when making treatment decisions; the need to provide emotional support at this vulnerable time; the importance of including the genetic counsellor in the multi-disciplinary team and the impact on the delivery of cancer genetic services with increasing demand for testing 73.

This overview of the psychosocial literature shows that treatment-focused genetic testing for BRCA1 and/or BRCA2 mutations is not associated with adverse psychological and quality of life outcomes. However, these studies included almost exclusively women with a family history that indicated an increased risk for hereditary breast/ovarian cancer, and very little is known about the psychosocial impact of treatment-focused genetic testing in women without a family history. This review also shows that very few data are currently available on: the anticipated implications of genetic testing for the patient and other family members; patient preferences in terms of timing of genetic testing information; mode of delivery of information; and preferred format and amount of information. Furthermore, no educational interventions have been developed to supplement expert advice and counselling of women considering treatment-focused genetic testing.

Given current funding constraints, the potential for routine testing in the future of newly diagnosed breast cancer patients also points to a need to develop and evaluate innovative patient education strategies as time-efficient means to supplement expert counselling provided by health professionals. Possible formats of resources include simple information sheets or more complex communication and decision aids. Communication aids may be used to facilitate and structure the discussion between the patient and the health professional and may also be tailored to the particular patient and taken home to be shared with other family members. Decision aids have been shown to improve understanding of the potential benefits and risks of different options and to assist patients to consider the personal importance of these options 74757677.