A clinical perspective on genetic counseling and testing during end of life care for women with recurrent progressive ovarian cancer: opportunities and challenges

Abstract

10–15% of invasive epithelial ovarian cancer is attributable to hereditary breast and ovarian cancer. The identification of BRCA1/BRCA2 mutations in women with ovarian cancer allows for accurate predictive genetic testing of their at-risk relatives, who can then avail themselves of early detection and risk reduction strategies. In the case of women with recurrent progressive ovarian cancer, the window of opportunity for genetic testing can be particularly limited. Here we describe our perspective on providing genetic counseling during these patients' end of life care, incorporating two illustrative examples from our clinical practice. While these situations pose unique challenges, they also present a significant opportunity to benefit the patient and her family. Further attention and research should be directed towards provision of genetic counseling and testing during end of life care.

Introduction

A relatively high proportion, 10–15%, of invasive epithelial ovarian cancers are attributable to mutations in the BRCA1 and BRCA2 genes [1–3]. In contrast, 5% or less of breast, colorectal, and endometrial cancers are attributable to identifiable hereditary cancer predisposition syndromes [4–7]. Germline BRCA1/BRCA2 mutations result in a hereditary predisposition to breast and ovarian cancer, with a lifetime risk of breast cancer up to 85% and lifetime risk of ovarian cancer up to 40% [8–11]. Identification of the familial BRCA mutation in the ovarian cancer patient allows family members to be tested for that specific mutation, with results that are clearly positive or clearly negative. However, if the opportunity to test the ovarian cancer patient is missed, then genetic testing of her unaffected relatives can yield ambiguous results. Women who test positive for a BRCA1/BRCA2 mutation are advised to undergo intensive screening and/or cancer risk-reducing surgeries; risk-reducing bilateral salpingo-oophorectomy in particular has been shown to reduce incidence of ovarian cancer as well as mortality in this high-risk population [12, 13]. BRCA1/BRCA2 genetic testing of ovarian cancer patients with suggestive personal/family histories, followed by predictive genetic testing of at-risk relatives, has been found to be cost-effective [14]. BRCA1/BRCA2 genetic testing of ovarian cancer patients with suggestive personal or family histories, therefore, has both high yield and high impact.

The majority of ovarian cancer is diagnosed at stage III or later, at which point risk of recurrence is high [15]. The long term prognosis for women with recurrent ovarian cancer remains poor, and therefore the window of opportunity for genetic testing can be limited. Three-quarters of ovarian cancer patients presenting to our institution have received initial treatment at another institution, and most of these women are seeking care for recurrent ovarian cancer [16]. We have found that many of these recurrent ovarian cancer patients have not previously had BRCA1/BRCA2 genetic testing, even when they have suggestive personal and family cancer histories [16, 17]. As well as providing outpatient genetic counseling services within our Gynecologic Oncology Center, we also offer inpatient genetic counseling to ovarian cancer patients who are at or near the end of life and would be unable to attend a traditional outpatient genetic consultation. This inpatient genetic consultation is truly the last opportunity for the patient to undergo genetic testing. Here we discuss our experience providing genetic counseling and testing to women with end-stage ovarian cancer, using two case examples to illustrate the unique challenges and opportunities posed by this situation. It is our wish to bring wider attention to this understudied topic, to encourage other genetics professionals to explore incorporating this likely underserved population into their clinical practice, and to suggest areas for further research.

Case examples

Case 1

The first patient is a 44 year-old Caucasian female who was diagnosed with FIGO Stage IIIC high-grade papillary serous ovarian cancer. She underwent tumor reductive surgery and received adjuvant chemotherapy with six cycles of carboplatin and paclitaxel. She developed recurrent disease approximately 4 years later, and was treated with surgery followed by multiple lines of chemotherapy over a 2 year period. During a subsequent hospitalization for complications related to recurrent progressive ovarian cancer, the patient's husband requested a genetics consultation, expressing particular concern regarding future implications for their teenage daughter. The patient had a strong family history of ovarian cancer, including a sister diagnosed with ovarian cancer in her 40s and their mother diagnosed with ovarian cancer in her 50s. The patient underwent comprehensive BRCA1/BRCA2 genetic testing, and a deleterious BRCA1 mutation was identified. The patient died shortly after her blood was drawn for genetic testing, and genetic test results were conveyed to her husband by telephone (the family lived out of state). Her husband, in turn, planned to discuss the genetic test results with at-risk relatives, including their daughter.

Case 2

The second patient is an African American female with a history of breast cancer diagnosed at age 41, and high grade serous ovarian cancer diagnosed at age 50. She underwent tumor reductive surgery, followed by six cycles of adjuvant chemotherapy with carboplatin and paclitaxel. She developed recurrent disease 8 months later and was treated with multiple lines of chemotherapy over a 2 year period. Her family history is significant for a sister who was diagnosed with breast cancer in her 30s, two maternal aunts with breast cancer in their 40s or 50s, and unspecified abdominal cancer in her mother in her 40s. She was seen by the genetic counselor 3 years after her initial diagnosis. At that time the patient agreed to BRCA testing, but due to financial constraints did not complete the testing. Three months later, the patient was admitted to the hospital with progressive disease. The financial issues related to genetic testing had been resolved in the interim. The genetic counselor met with the patient and her daughters for further discussion during her hospitalization, and blood was drawn for genetic testing. The patient was discharged to an inpatient hospice facility 1 week later and passed away the following week. The results of the genetic testing were discussed with the patient's daughters approximately 2 weeks after the patient's death. The patient tested positive for a BRCA1 mutation.

The inpatient genetic consultation: genetic counseling issues

The genetic counseling conducted at the bedside of these patients differed significantly from a traditional outpatient genetic consultation. We sought a balance between providing all of the information necessary for an informed decision about genetic testing, while not demanding more time and attention than the patient or their family had to give at that moment. Given the multiple issues and decisions facing ovarian cancer patients at the end of life, we do place emphasis on simplifying the genetic counseling process as much as possible, condensing the information to a clear and simple message, as has been previously recommended [18]. One obvious example of a difference in information presented is that, at a typical outpatient genetic consultation, considerable time is devoted to discussing the medical implications of the genetic test results for the patient. In the case of terminal ovarian cancer, this information is no longer relevant.

The patient's physical state, and the patient and family's emotional state, must be given consideration. In case example 1, the family felt strongly that it was important to make the genetic testing information available to the patient's daughter and other relatives and wanted to proceed with genetic counseling for this reason. At the same time, the family was actively grieving the imminent loss of the patient and had limited resources to devote to discussing specific details at that time. Substantial additional genetic counseling, therefore, was conducted with the patient's husband later during results disclosure. In case example 2, the patient's attention waxed and waned during the consultation due to her disease state. Since she had received genetic counseling prior to this time, we were able to very much condense the information we presented to her, and also were able to discuss implications for family members directly with the family members present.

We do find it important to still obtain a full (at least three generation) pedigree in these cases, for two reasons: It allows us to identify the at-risk relatives and provide appropriate guidance to the family about who to share genetic test results with, and it also facilitates risk assessment. Both of our examples tested positive for a BRCA1 mutation, which was clearly suggested by their personal and family history. In other cases, consideration would need to be given to whether additional genetic testing (for Lynch syndrome, for example) may be needed, and whether DNA banking should be recommended, since there may well not be the opportunity to pursue a second round of genetic testing if the first test is uninformative. Pedigree construction can be a time-consuming process. However, family members can often supply most if not all of the needed information, thus sparing the patient this effort while also actively engaging the family in the genetic counseling. In both case examples, we had the opportunity to converse with several family members; in case example 1, both the spouse and the patient's brother were present, and in case example 2, two of the patient's daughters were present.

Given the multiple issues facing the patient and family during end of life care, one may well ask whether genetic counseling in this context is appropriate—are we simply burdening the family with another worry at an already worrisome time? Our experience has been that patients are already concerned about family members' cancer risks prior to genetic counseling. Rather than creating an additional burden, genetic counseling and testing and the subsequent risk-reduction options available for family members can be seen by the patient as a tangible way to address this pre-existing concern, as well as a source of hope for a better outcome for their relatives than what they themselves are experiencing. Many ovarian cancer patients are interested in undergoing genetic testing to provide information for relatives; a recent survey found that 87% would be willing to have genetic testing solely for the purpose of helping their family [19].

Disclosure of genetic test results

In both of our case examples, genetic test results became available only after the patient's death and were therefore discussed with next of kin. The very real possibility that the patient may die before the genetic test results are available must always be addressed in this setting, and the patient's and family's preferences for who to contact and how to contact them should be elicited. Again, the frequent presence of family members at the bedside affords the opportunity to include them in the genetic counseling process. Since we had established contact with these family members at the initial inpatient genetic consultation, we were able to plan ahead of time how the results would be disclosed directly to family members if necessary, and those family members were prepared to receive and act upon the results.

The timing of results disclosure should also be considered, and should be based on the family's preferences. In both of our case examples, we alerted the designated contact to the availability of the genetic test results as soon as they were ready, and their subsequent responses span a wide range. In case example 1, the patient's husband did not wish to discuss the results until nearly a year later; before that, he was not ready to discuss the implications with their daughter and did not feel she was ready either. In case example 2, the patient's daughters were anxious to receive the results, because they wished to undergo predictive genetic testing as soon as possible.

Areas for future research

Our clinical experience with genetic counseling and testing during end of life care is comprised of ovarian cancer patients with personal/family histories clearly suggestive of a known hereditary cancer predisposition syndrome, who were either previously known to the genetics service or whose family or healthcare provider requested the genetics consult. It seems likely that there are other end-of-life oncology patients who could benefit from genetic counseling and testing that are not being identified. Given the high proportion of ovarian cancer that is hereditary and the increasing public awareness of BRCA1/BRCA2 genetic testing, the barriers to identifying appropriate referrals may be lower here than in other cancers. We suggest that one area for future research would be to examine ways to more systematically identify patients in end-of-life care who would be appropriate to refer for genetic counseling, and to raise awareness among healthcare providers involved in end-of-life care about the availability and advisability of genetic counseling and genetic testing for their patients.

Physicians and other health care providers may be reluctant to bring up hereditary cancer genetic testing during end of life care, because they may perceive it as an additional burden at an already difficult time. It would be important to assess the comfort level of healthcare providers involved in end-of-life care in bringing up genetic counseling, as well as what the perceived barriers are, so that these may be addressed.

Conclusion

Ideally, genetic counseling and testing would be offered to all at-risk ovarian cancer patients at diagnosis or early in their disease course. The potential utility of targeted therapies such as PARP inhibitors further emphasizes the importance of BRCA1/BRCA2 genetic testing for ovarian cancer patients near the time of their initial diagnosis [20]. However, it must be acknowledged that in the real world genetic testing does not always occur early in the disease course, for many different reasons. Both recurrent cancer patients and their clinicians tend to overestimate lifespan [21], and thus could find themselves facing end-of-life issues with little prior warning. Realistically, improving identification of at-risk patients who could benefit from genetic counseling and testing will necessitate a concerted effort throughout the disease course. A recent study at our institution found that, while identification and referral for genetic counseling of at-risk ovarian cancer patients has improved over time, a significant number of high-risk patients continue to be missed [16]. In addition, Quillin et al. [22] found that 21% of a sample of dying cancer patients were at significant risk for hereditary cancer, but almost half of these high-risk patients knew “almost nothing” about genetic testing for cancer risk.

Given the significance of genetic test results for family members, efforts should be made to maximize the availability of genetic counseling and testing to ovarian cancer patients at risk for hereditary cancer at all phases of the disease process, including during end-of-life care. Genetic counseling and testing for women with ovarian cancer nearing the end of life provides significant information to family members, and in our experience both patients and their families appreciate and can benefit from the process. The literature regarding genetic counseling and testing during end of life oncology care is sparse, but there is general agreement that further attention and research efforts should be directed towards addressing this population's needs [23, 24]. In particular, we feel that further research is needed on best practices for identifying and referring appropriate patients and raising awareness among healthcare providers engaged in end-of-life oncology care.