Originally published as JCO Early Release 10.1200/JCO.2004.04.086 on April 5 2004

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Impact of BRCA1/BRCA2 Counseling and Testing on Newly Diagnosed Breast Cancer Patients

From the Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC; and the Department of Psychiatry, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA.

Address reprint requests to Marc D. Schwartz, MD, Georgetown University School of Medicine, Lombardi Comprehensive Cancer Center, Cancer Control, 2233 Wisconsin Ave, NW, Suite 317, Washington, DC 20007; e-mail: schwartm{at}georgetown.edu

	ABSTRACT

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PURPOSE: Approximately 5% to 10% of newly diagnosed breast cancer patients carry a BRCA1 or BRCA2 mutation. Given these patients' high risk for contralateral breast cancer, bilateral mastectomy is increasingly considered a treatment option for newly diagnosed BRCA1/2 carriers. In the present study, we prospectively evaluated the impact on surgical decision-making of pretreatment genetic counseling and BRCA1/BRCA2 testing among breast cancer patients at high-risk for carrying a mutation.

PATIENTS AND METHODS: Participants were 194 newly diagnosed breast cancer patients who had not yet received definitive surgical treatment and who had at least a 10% prior probability of carrying a BRCA1/2 mutation. Participants were offered free genetic counseling and rapid BRCA1/2 testing. Primary analyses focused on the impact of BRCA1/2 test result on subsequent breast cancer surgical treatment.

RESULTS: Forty-eight percent of patients who were found to carry a BRCA1/2 mutation chose bilateral mastectomy as their definitive breast cancer surgery. In contrast, 24% of patients in whom no mutation was detected and 4% of test decliners opted for bilateral mastectomy. Additional predictors of bilateral mastectomy included patients' self-reports of physician recommendations for BRCA1/2 testing and bilateral mastectomy.

CONCLUSION: This study highlights patient interest in and the technical feasibility of offering presurgery BRCA1/2 testing to high-risk patients. Most importantly, these results demonstrate that BRCA1/2 test results significantly affect patients' surgical decision-making. The availability of genetic counseling and testing could serve as a valuable aid to patient decision-making for newly diagnosed breast cancer patients at high-risk for carrying a mutation.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Most research on the impact of genetic testing for inherited breast and ovarian cancer susceptibility has focused on breast and ovarian cancer survivors and their unaffected relatives. There have been no reports documenting the impact of genetic testing for inherited cancer risk among newly diagnosed breast cancer patients. As many as 5% to 10% of breast cancer patients may carry a BRCA1 or BRCA2 (BRCA1/2) mutation,¹ and therefore have a greatly elevated risk of contralateral breast cancer.^2-4 Although breast-conserving therapy (BCT) remains the treatment of choice for most newly diagnosed breast cancer patients,⁵ women at risk for carrying a BRCA1/2 mutation may also consider more extensive surgery, such as bilateral mastectomy (BLM), to treat their current cancer and reduce their risk for contralateral breast cancer.

Given recent evidence demonstrating high rates of contralateral and late ipsilateral breast cancer, BLM at the time of diagnosis has been suggested as a reasonable strategy for BRCA1/2 mutation carriers.^6-8 Genetic counseling and testing at the time of initial breast cancer diagnosis could be a valuable aid to surgical decision-making among high-risk breast cancer patients. However, the management of hereditary breast cancer and the role of genetic testing among newly diagnosed patients remain controversial.^9-11 Potential advantages of presurgical BRCA1/2 testing are that carriers who opt for immediate BLM can avoid unnecessary radiation treatment and a possible second surgery, should they decide later to remove the contralateral breast. Disadvantages include the possibility of an uninformative test result, the added stress associated with undergoing BRCA1/2 testing immediately following diagnosis, and the possibility of delaying definitive surgical treatment to await test results. Furthermore, given the efficacy of BCT among carriers with early-stage disease,⁶ the low mortality rate for contralateral breast cancer,^12,13 and the availability of alternate risk-reduction options, such as tamoxifen^14,15 and prophylactic oophorectomy,^16,17 there are questions regarding the benefits of immediate BLM.¹⁰

Although controversial, BLM is becoming an increasingly accepted option for newly diagnosed breast cancer patients.^6,7 Despite increased acceptance and current guidelines suggesting genetic referral for patients in which hereditary breast cancer is suspected,¹⁸ there is a lack of empirical data to guide the clinical integration of this technology in the management of newly diagnosed breast cancer. In the present report, we evaluated the impact of BRCA1/2 testing on surgical treatment decisions among newly diagnosed high-risk breast cancer patients. We predicted that the receipt of a positive BRCA1/2 test result would be associated with an increased likelihood of choosing BLM as definitive surgical treatment.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Study Population
This study was approved by the institutional review board at Georgetown University. Participants were 194 newly diagnosed breast cancer patients who were eligible for genetic testing and who completed baseline assessment. Patients self-referred into the study by contacting the program directly (typically following a physician recommendation) or by indicating their desire to participate on a standard family history screening form that was routinely completed in the waiting room of participating physicians. Eligibility for genetic testing was determined by standard clinical criteria used by the Lombardi Comprehensive Cancer Center's Cancer Assessment and Risk Evaluation program.^19-21 These criteria were designed to identify individuals with a personal/family history of cancer that was roughly consistent with a minimum 10% prior probability of carrying a BRCA1/2 mutation based on published reports.^18,22-25 For example, non-Jewish breast cancer patients were eligible if they were diagnosed before age 50 years and had a first-degree relative who was diagnosed with breast cancer before 50 years of age or ovarian cancer at any age. Jewish patients were eligible if they were diagnosed before age 50 years, regardless of family history or if they were diagnosed before age 60 years and had a first-degree relative with ovarian cancer (at any age) or breast cancer before 50 years of age.

In addition to the personal and family history criteria, to be eligible for this study patients had to be female, newly diagnosed with ductal carcinoma-in-situ to stage IIIa breast cancer and not yet received definitive local treatment. Definitive treatment was defined as mastectomy (unilateral or bilateral) or BCT, including the initiation of radiation treatment. Thus, patients who had undergone lumpectomy but had yet to initiate radiation treatment remained eligible for participation.

Two hundred twenty-seven eligible patients were identified, and 203 (89%) completed a baseline telephone assessment. We were unable to obtain definitive surgery data on nine patients (4%; all of whom had declined BRCA1/2 testing). Thus, our final sample of 194 patients represented 85% of those eligible for the study.

Procedures
Participants were referred from surgical, medical oncology, and radiation oncology practices at Lombardi Comprehensive Cancer Center and community practices. Interested patients were contacted by the study staff to assess eligibility. Eligible patients completed a structured telephone interview that assessed sociodemographic data, personal/family history of cancer, psychosocial factors, and physician recommendations. Subsequently, participants were invited to participate in a pretest education/counseling session with a genetic counselor or an oncology nurse educator trained in genetic counseling. The content of this 1.5- to 2-hour session has been described elsewhere.²⁶ In brief, this session was comparable with traditional genetic counseling for hereditary breast cancer, but with an added focus on the elevated risks for second breast cancers, risks and benefits of testing at the time of initial diagnosis, and data regarding the efficacy of BCT and BLM for BRCA1/2 mutation carriers.

Following this counseling session, interested participants provided a blood sample for BRCA1/2 mutation testing. Jewish probands were offered testing for a panel of the three founder mutations common in that population.²⁷ Non-Jewish probands were offered full BRCA1/2 testing. Although the methods of testing varied, the methods used (eg, sequencing, conformation-sensitive gel electrophoresis) are thought to detect most deleterious mutations in the gene; however, none of the methods is 100% sensitive.²⁸ Given the time-sensitive nature of this testing, efforts were made to obtain test results within 2 to 3 weeks (mean, 15 days; standard deviation, 8 days).

When test results were available, a disclosure session was scheduled. Because of time constraints, disclosure sessions were frequently conducted by telephone. These sessions lasted approximately 1 hour and were comparable with traditional BRCA1/2 genetic counseling disclosure sessions,²⁶ with an added emphasis on the implications of the test result for surgical breast cancer treatment. Overall, 27 participants (14%) declined genetic testing. Participants who chose to be tested received one of four possible test results. Participants in whom a deleterious mutation was identified (n = 31) were counseled regarding their increased risk for ipsilateral and contralateral breast cancer and ovarian cancer. Patients in whom full BRCA1/2 sequencing did not identify a deleterious mutation (n = 62) were counseled that although this test result ruled out the vast majority of known deleterious BRCA1/2 mutations, the possibility of hereditary cancer due to a false-negative result or a mutation in another susceptibility gene could not be definitively excluded. Similarly, patients found to carry a variant of uncertain clinical significance (n = 19) were counseled that this "ambiguous" result could not rule out hereditary breast cancer. Finally, Ashkenazi Jewish patients who tested negative for the three founder mutations ("panel negative"; n = 55) were counseled that their risk for carrying another BRCA1/2 mutation was low.^17,29-30 However, those with an extensive family history and an early age of breast cancer diagnosis were counseled that there remained a possibility of an undetected BRCA1 or BRCA2 mutation, or a mutation in another cancer susceptibility gene.

Patients who received uninformative test results (ie, "panel negative," "BRCA1/2 negative," or "ambiguous") were counseled regarding their residual risk for contralateral breast cancer. This counseling was individualized based on the patient's personal and family history of breast and ovarian cancer. As discussed earlier, Ashkenazi Jewish patients with no family history of breast or ovarian cancer were counseled that their residual risk for carrying a BRCA1/2 mutation was low, and their risk for developing a second breast cancer was comparable with sporadic breast cancer patients. All other patients with uninformative test results (including Ashkenazi Jewish patients with a family history of breast and/or ovarian cancer) were told that their risks of developing a second cancer could still be higher than the risk to women with sporadic cancer. It was explained that a positive family history of breast cancer is an established risk factor for the development of contralateral breast cancers³¹ but that this risk level does not approach the magnitude of risk encountered in women with a deleterious BRCA1/2 mutation. The limited data about the rate of false-negative BRCA1/2 test results and the subsequent difficulty in quantifying residual risks of carrying a mutation and of developing a second breast cancer were explained to all patients who received uninformative results.

Because the "panel negative," "ambiguous," and "BRCA1/2 negative" groups did not differ in their surgical decisions (n = 136; ^2₂ = 1.18; P = .56), these groups were combined into a single "uninformative" group (n = 136) for subsequent analyses. Participants who declined genetic testing, but completed a baseline survey (n = 27) were classified as "decliners." We have used identical classifications in previous research.^21-23

Measures
Sociodemographic and family history variables. At baseline, we assessed age, race, ethnicity, marital status, education, employment, and the number of first- and second-degree relatives affected with breast or ovarian cancer.

Stage at diagnosis. We abstracted stage at diagnosis from participant medical records. We were unable to obtain complete staging data for 22 participants (11%) because of incomplete ascertainment of medical records. In multivariate analyses involving stage, we used a modal substitution for missing data. (Sensitivity analyses confirmed that the results were identical with and without the modal substitution.)

Adjuvant chemotherapy. Receipt of adjuvant chemotherapy was assessed via patient self-report at follow-up interviews. All patients who reported receipt of adjuvant chemotherapy at any follow-up time point (1, 6, and 12 months postbaseline) were classified as having received adjuvant chemotherapy.

Psychological variables. At baseline, we measured cancer-specific distress with the reliable (Cronbach's coefficient = 0.82) 15-item Impact of Events Scale.³² We measured anxiety with the reliable (Cronbach's = .92) State subscale of the State-Trait Anxiety Inventory.³³ We measured cancer-specific quality of life with the summary score of the reliable (Cronbach's = .87) 27-item Functional Assessment of Cancer Therapy-General questionnaire.^34,35

Patient report of genetic testing recommendation. At baseline, patients were asked whether they had received a specific recommendation for testing from each of their physicians (surgeon, medical and radiations oncologists). We categorized patients into those who reported that they received at least one recommendation to undergo testing (n = 100) versus those who did not (n = 87). Seven participants declined to answer this question. All of these participants ultimately declined BRCA1/2 testing.

Patient report of surgical recommendation. At baseline, we asked patients whether their surgeon had made a surgical recommendation. For patients who reported they had received a recommendation, we asked whether the surgeon had provided a specific recommendation or a recommendation conditional on the receipt of a BRCA1/2 test result (ie, recommendation for BLM in the event of positive BRCA1/2 test result). For analysis, we categorized patients into those who reported either an absolute or conditional recommendation for BLM (n = 39) versus those who reported no recommendation for BLM (n = 148). Seven participants declined to answer this question. All of these participants ultimately declined BRCA1/2 testing.

Definitive treatment decision. Treatment decision was abstracted from the genetic counselors' follow-up records. Patients who had surgery to remove both the affected and contralateral breast were classified as having BLM. Patients who had surgery to remove only the affected breast were classified as having unilateral mastectomy (UM). Patients who received a lumpectomy plus radiation to the affected breast were classified as having BCT.

Data Analysis
Descriptive statistics were generated to characterize the sample in terms of sociodemographics, medical variables, and family history. Next, we looked at bivariate predictors of treatment decisions using ² and t tests. To identify independent predictors of the decision to obtain a BLM, we used multiple logistic regression with backward elimination of nonsignificant variables.

	RESULTS

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Sample Characteristics
As seen in Table 1, the sample was predominantly white (85%), college-educated (84%), married (69%), and employed (59%). The mean age of participants was 43 years (standard deviation = 9 years). Twenty-five percent of the sample had at least two first-degree relatives with breast or ovarian cancer. The majority of participants were diagnosed with ductal carcinoma-in-situ or stage I breast cancer (63%), chose conservative therapy (53%), and ultimately received adjuvant chemotherapy (59%). Of the 194 participants in the study, 167 (86%) chose to receive BRCA1/2 test results.

View larger version (23K): [in this window] [in a new window]   Fig 1. Definitive breast cancer surgery by BRCA1/BRCA2 genetic test result. BCT, breast-conserving therapy; UM, unilateral mastectomy; BLM, bilateral mastectomy.

Predictors of Bilateral Mastectomy
Because only one decliner opted for BLM, we eliminated decliners from subsequent analyses. Thus, among all patients who chose to undergo genetic testing, we evaluated bivariate (Table 2) and continuous-variable (Table 3) associations between baseline sociodemographic, psychosocial, family-history, and medical variables with receipt of BLM versus UM/BCT.The following variables exhibited significant (P < .05) bivariate association with the receipt of BLM: test result (n = 167; ^2₁ = 7.17; P = .007), number of affected first-degree relatives (t¹⁶⁵ = 2.0; P = .05), tumor-node-metastasis system stage (n = 153; ^2₁ = 4.72; P = .03), physician BRCA1/2 testing recommendation (n = 167; ^2₁ = 15.42; P < .001), and surgeon's recommendation for BLM (n = 167; ^2₁ = 20.41; P < .001).

	DISCUSSION

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This is the first large-scale prospective study to provide evidence that BRCA1/2 genetic testing has a clinically significant impact on surgical decision-making among newly diagnosed breast cancer patients. Overall, 48% of patients who received a positive BRCA1/2 test result opted for BLM as their definitive breast cancer treatment. In contrast, 24% of those who received uninformative test results and 4% of those who declined testing opted for BLM. Importantly, the impact of test result remained even after controlling for additional predictors, such as surgeon's treatment recommendation. These results are consistent with a previous report on a small sample of newly diagnosed patients.³⁶

These results demonstrate that many newly diagnosed breast cancer patients are interested in and willing to undergo presurgery genetic counseling and testing if it is made available to them. Furthermore, among those who chose to be tested, the majority (77%) received their test results before the initiation of their definitive local treatment. This demonstrates the feasibility of offering BRCA1/2 counseling and testing as an aid to treatment decision-making for high-risk patients. In practice, not all high-risk patients will require such rapid testing to use test results to guide treatment choices. For example, patients who proceed with adjuvant chemotherapy following local excision could delay their definitive treatment decision until the conclusion of chemotherapy. At that point, they could decide whether to proceed with radiation treatment (BCT) or whether to opt for UM or BLM. In the present study, regardless of whether patients delayed their decision-making until the conclusion of adjuvant chemotherapy, receipt of a positive test result remained significantly associated with BLM (data not shown).

Not surprisingly, these results also suggest that physician recommendations were an important determinant of surgical decisions. Specifically, patients who reported that they had received a recommendation to undergo BRCA1/2 testing or to consider BLM were significantly more likely to choose BLM. Of course, patient reports of physician recommendations may not be reliable. Thus, future studies should measure actual physician recommendations rather than rely on patient reports. Although these results suggest that physician recommendation may be an important determinant of surgical decision-making, it is also likely that the receipt of genetic information may be of value to physicians in formulating management recommendations.³⁷ In the present study, we did not assess whether the patient's test result had an influence on physician treatment recommendations. However, it is likely that the additional information provided by testing informed subsequent treatment discussions between patients and physicians.

We were surprised by the 24% rate of immediate BLM among participants who received uninformative test results. In the only previous report on this population, 12% of patients who received uninformative results opted for BLM.³⁶ The results of the present study raise concerns that pretreatment genetic counseling might itself lead to more aggressive surgical treatment. However, our follow-up analyses suggest this is not the case. Compared with patients who received uninformative results and who did not opt for BLM, patients with uninformative results who did choose BLM had a significantly greater family history of breast and ovarian cancer. This suggests that patients with uninformative results opted for BLM because they still faced elevated risks of contralateral breast cancer. Similarly, among patients with uninformative results, Ashkenazi Jewish participants were less likely to obtain a BLM, compared with non-Jewish participants. Again, this is consistent with an association between residual risk and BLM among patients with uninformative results.

A chart review of all patients with uninformative results who opted for BLM suggests several possible explanations for the seemingly high rate of BLM. First, nearly half of all patients with uninformative results who obtained a BLM had made this decision before their initial genetic counseling session. Of the remaining patients with uninformative results who chose BLM, virtually all reported at least one other risk factor (eg, lobular cancer, previous breast biopsies on contralateral breast, ineligibility for BCT, failure of routine mammogram to detect current cancer) that was likely to have contributed to their decision. Finally, in unpublished preliminary data from our ongoing research with breast cancer survivors, we have found that 22% of participants had obtained a BLM at the time of study entry (ie, before genetic counseling). Thus, the 24% rate of BLM in the present study is comparable to the BLM rate among breast cancer survivors who have self-referred to a clinical genetic counseling program.

Another important clinical finding was that receipt of a positive test result was not associated with decreased use of BCT. Rather, compared with patients who declined testing or received uninformative test results, carriers were more likely to obtain a BLM and less likely to obtain a UM. This is not surprising, given the equivalent rates of local control for BCT and UM among mutation carriers.^6-8 Thus, there would be little reason for a carrier who is eligible for BCT to choose UM. Similarly, among carriers not eligible for BCT, our data suggest the vast majority will opt for BLM. In fact, only one mutation carrier in our sample chose to receive UM. These data suggest that genetic testing may be of particular benefit for women who are considering UM or are not eligible for BCT.

There are several limitations to this study. First, we do not know how many eligible patients were not referred to or enrolled onto our study. Thus, we could not evaluate the prevalence of different surgical decisions in this population. Second, because we offered free counseling and testing, the generalizability of these results must be established by additional studies. Finally, this study did not involve random assignment. To evaluate definitively the impact of genetic counseling on surgical decision-making, a randomized clinical trial would be required.

Despite these limitations, the present report provides the strongest evidence to date of the effects of BRCA1/2 testing on treatment decision-making among newly diagnosed breast cancer patients. The impact of testing on the subsequent treatment decisions suggests that testing should be offered to interested high-risk patients.^37-38 However, given the lack of data regarding the survival benefits and quality-of-life outcomes of BLM, additional research is needed to determine the optimal timing of genetic testing with regard to surgical decision-making.^10,39 Until future research determines the relative benefits of genetic referral at the time of diagnosis, recommendations to undergo BRCA1/2 testing must be based on patient preferences. The central role of patient preference in this decision underscores the need for access to genetic counseling that is specifically tailored to this population.²⁶

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Supported by grants RO1 CA/HG74861 (M.D.S.) and KO7 CA65597 (M.D.S.).

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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Submitted April 10, 2003; accepted December 21, 2003.

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